Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: BCL2L13 is a mitochondrial protein that acts at the mitochondrion (mitophagy receptor and pro-apoptotic activity at the mitochondrial outer membrane). Reason: Mitochondrial localization/activity is strongly and consistently supported; the mitochondrion is the principal functional compartment. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria file:human/BCL2L13/BCL2L13-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion membrane
GO:0016020 membrane	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: BCL2L13 is a single-pass tail-anchored membrane protein; generic membrane localization is correct but uninformative relative to the specific mitochondrial membrane. Reason: The generic membrane term is subsumed by the more specific and well-supported mitochondrial (outer) membrane localization. Supporting Evidence: file:human/BCL2L13/BCL2L13-uniprot.txt Single-pass membrane protein
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: A nuclear localization is reported in UniProt, largely for the truncated isoform 1 that lacks the transmembrane anchor; it is secondary to the mitochondrial role. Reason: Nuclear localization is documented (especially for the short nuclear isoform) but is not the functional compartment for the conserved mitophagy/mitochondrial activities. Supporting Evidence: file:human/BCL2L13/BCL2L13-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Nucleus
GO:0006915 apoptotic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: BCL2L13/Bcl-rambo can promote apoptosis (originally described as a pro-apoptotic BCL-2 homolog), an InterPro-based transfer consistent with the experimental literature. Reason: A pro-apoptotic capacity is genuine but context/overexpression-dependent and secondary to the conserved mitophagy-receptor function. Supporting Evidence: PMID:11262395 its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs
GO:0031966 mitochondrial membrane	IEA GO_REF:0000044	ACCEPT	Summary: BCL2L13 is anchored in the mitochondrial membrane (outer membrane), consistent with its tail-anchor and UniProt subcellular location. Reason: Well-supported core localization; the mitochondrial membrane is where BCL2L13 acts. Supporting Evidence: file:human/BCL2L13/BCL2L13-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion membrane
GO:0042981 regulation of apoptotic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: As a BCL-2-family protein with pro-apoptotic activity, BCL2L13 participates in regulation of apoptosis; an InterPro-based transfer consistent with the literature. Reason: Supported by the apoptosis literature but context-dependent and secondary to the mitophagy-receptor function. Supporting Evidence: PMID:11262395 Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a proteome-scale interaction map does not identify an interpretable BCL2L13 function.
GO:0005515 protein binding	IPI PMID:17360363 Legionella pneumophila inhibits macrophage apoptosis by targ...	MARK AS OVER ANNOTATED	Summary: This protein-binding annotation reflects the specific interaction of Bcl-rambo with the Legionella effector SidF (which neutralizes it to block host apoptosis); as bare protein binding it is uninformative. Reason: The underlying SidF interaction is meaningful and confirms Bcl-rambo as a pro-death host target, but the generic protein binding term does not capture this; no specific GO binding term for a bacterial effector applies. Supporting Evidence: PMID:17360363 SidF contributes to apoptosis resistance in L. pneumophila-infected cells by specifically interacting with and neutralizing the effects of BNIP3 and Bcl-rambo, two proapoptotic members of Bcl2 protein family.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a proteome-scale interactome map is not functionally specific.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a disease-interactome perturbation study is not functionally specific.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	MARK AS OVER ANNOTATED	Summary: High-throughput alternative-splicing interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a large-scale splicing-interactome study is not functionally specific.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a large-scale interactome study is not functionally specific.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a reference binary interactome map is not functionally specific.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: High-throughput neurodegenerative-disease interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a disease-interactome study is not functionally specific.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a cell-specific interactome remodeling study is not functionally specific.
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: Orthology-based transfer of mitochondrial activity, consistent with the well-supported mitochondrial localization/function of BCL2L13. Reason: Consistent with the core mitochondrial compartment where BCL2L13 acts. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence-based mitochondrial localization, consistent with the literature. Reason: Directly supported core localization. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteome localization, consistent with BCL2L13 being a mitochondrial protein. Reason: Consistent with the well-supported core mitochondrial localization. Supporting Evidence: PMID:34800366 mitochondrial proteome
GO:0006915 apoptotic process	NAS PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi...	KEEP AS NON CORE	Summary: The founding Bcl-rambo study reports that overexpression induces caspase-dependent apoptosis, providing the basis for the apoptotic-process annotation. Reason: A pro-apoptotic role is supported but is overexpression-driven and context-dependent; secondary to the conserved mitophagy-receptor function. Supporting Evidence: PMID:11262395 its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs
GO:0005739 mitochondrion	NAS PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi...	ACCEPT	Summary: The founding study localized Bcl-rambo to mitochondria. Reason: Directly supported core localization. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria
GO:0008656 cysteine-type endopeptidase activator activity involved in apoptotic process	NAS PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi...	KEEP AS NON CORE	Summary: BCL2L13-induced apoptosis is caspase-dependent (blocked by caspase inhibitors/IAPs), and UniProt states it may promote caspase-3 activation; this caspase-activator annotation captures a contextual pro-apoptotic effect rather than a direct, conserved molecular function. Reason: The caspase-3 activation is indirect/context-dependent (overexpression-driven apoptosis) and is not the conserved core molecular function (mitophagy-receptor activity); retained as a non-core apoptosis-related annotation. Supporting Evidence: PMID:11262395 its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs file:human/BCL2L13/BCL2L13-uniprot.txt May promote the activation of caspase-3 and apoptosis.
GO:0016020 membrane	IDA PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi...	MARK AS OVER ANNOTATED	Summary: Bcl-rambo's cell-death activity maps to its membrane-anchored C-terminal domain; generic membrane localization is correct but uninformative. Reason: Subsumed by the specific mitochondrial (outer) membrane localization. Supporting Evidence: PMID:11262395 the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain
GO:0140580 mitochondrion autophagosome adaptor activity	IDA PMID:26146385 Bcl-2-like protein 13 is a mammalian Atg32 homologue that me...	NEW	Summary: BCL2L13/Bcl2-L-13 is an outer-mitochondrial-membrane mitophagy receptor that binds LC3 through its WXXI/LIR motif and recruits autophagy machinery to mitochondria. Reason: The PN-guided review identified that the YAML's proposed "mitophagy receptor activity" request is already covered by GO:0140580. This existing MF should be added instead of requesting a new term. Supporting Evidence: PMID:26146385 Bcl2-L-13 binds to LC3 through the WXXI motif and induces mitochondrial fragmentation and mitophagy
GO:0000423 mitophagy	IMP PMID:26146385 Bcl-2-like protein 13 is a mammalian Atg32 homologue that me...	NEW	Summary: BCL2L13 promotes selective autophagy of mitochondria, and knockdown attenuates damage-induced mitochondrial fragmentation and mitophagy. Reason: The review already treats mitophagy as the core biological process, but the seeded existing_annotations lacked a manual recommendation for the BP term. This adds the existing GO process term with primary evidence. Supporting Evidence: PMID:26146385 Knockdown of Bcl2-L-13 attenuates mitochondrial damage-induced fragmentation and mitophagy

Core Functions

BCL2L13/Bcl-rambo functions as a mitophagy receptor at the mitochondrial outer membrane. As the mammalian functional homolog of yeast Atg32, it binds Atg8-family proteins (LC3/GABARAP, including GABARAPL2) via an LC3-interacting region to recruit autophagy machinery to mitochondria, promoting mitochondrial fragmentation and selective autophagy of mitochondria.

Molecular Function:

mitochondrion autophagosome adaptor activity

Directly Involved In:

mitophagy

Cellular Locations:

mitochondrial membrane

Supporting Evidence:

file:human/BCL2L13/BCL2L13-uniprot.txt
Q9BXK5; P60520: GABARAPL2; NbExp=4; IntAct=EBI-747430, EBI-720116;
file:human/BCL2L13/BCL2L13-uniprot.txt
GO:0000423; P:mitophagy; IEA:Ensembl.

BCL2L13 has a context-dependent pro-apoptotic activity. Originally characterized as a BCL-2 homolog whose overexpression induces caspase-dependent apoptosis via its membrane-anchored C-terminal region (not its BH motifs), it can promote caspase-3 activation and does not heterodimerize with other BCL-2-family members; it is a target of the Legionella effector SidF.

Directly Involved In:

apoptotic process

Cellular Locations:

mitochondrial membrane

Supporting Evidence:

PMID:11262395
its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs
PMID:11262395
the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:11262395

Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:17360363

Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25910212

Widespread macromolecular interaction perturbations in human genetic disorders.

PMID:26871637

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

PMID:26146385

Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation.

BCL2L13 is the mammalian functional homolog of yeast Atg32; it binds LC3 through a WXXI/LIR motif and induces both mitochondrial fragmentation and mitophagy. The BH domains mediate fragmentation while the WXXI motif facilitates mitophagy.
BCL2L13 induces mitochondrial fragmentation in the absence of DRP1/DNM1L and induces mitophagy in Parkin-deficient cells, placing it in a ubiquitin-independent, Parkin-independent receptor-mediated mitophagy pathway, and it can rescue mitophagy in Atg32-deficient yeast.

PMID:36589739

Biological properties of the BCL-2 family protein BCL-RAMBO, which regulates apoptosis, mitochondrial fragmentation, and mitophagy.

BCL-RAMBO/BCL2L13 is an integral mitochondrial outer-membrane protein with BH1-BH4 domains, a BHNo region containing the LC3-interacting region (human LIR WQQI), and a C-terminal transmembrane anchor; it functions as a mitophagy receptor recruiting ATG8-family proteins (LC3/GABARAP) via the LIR motif.
Phosphorylation near the LIR (Ser272 in mouse numbering) tunes LC3 binding and mitophagic activity; PGAM5 acts as a negative regulator by dephosphorylating BCL2L13, and BCL2L13 is reported to recruit the ULK1 complex to the mitochondrial outer membrane to initiate mitophagy.

PMID:39175772

BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.

BCL2L13 localizes to mitochondria, ER, and mitochondria-associated membranes (ER-mitochondria contact sites) and regulates ER-mitochondria calcium homeostasis; its knockdown alters cytosolic calcium release and mitochondrial calcium uptake without changing the number of ER-mitochondria contact sites, indicating a functional rather than structural contact-site role.
Loss of Bcl2l13 in zebrafish impairs skeletal muscle structure and function and decreases mitochondrial complex activity, supporting a physiological role in muscle bioenergetics and calcium handling.

PMID:37660127

BCL2L13 promotes mitophagy through DNM1L-mediated mitochondrial fission in glioblastoma.

In glioblastoma, BCL2L13 is upregulated and promotes mitochondrial fission and high mitophagy flux by targeting DNM1L (DRP1) at the Ser616 site, promoting tumor proliferation and invasion; this DNM1L-dependent mechanism is context-specific and contrasts with DRP1-independent fragmentation reported elsewhere.

PMID:38494498

YME1L-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions.

BCL2L13 was identified by LC-MS/MS as an interacting partner of the inner mitochondrial membrane protease YME1L; YME1L promotes phosphorylation of BCL2L13, strengthening BCL2L13-LC3 binding and enhancing mitophagy to restrain renal tubular epithelial cell senescence in diabetic kidney disease models.

PMID:34193180

Down-regulation of BCL2L13 renders poor prognosis in clear cell and papillary renal cell carcinoma.

BCL2L13 expression is decreased in clear-cell and papillary renal cell carcinoma and lower expression correlates with poorer prognosis independently of tumor grade; BCL2L13 positively correlates with SLC25A4 (ANT), implicated as a downstream effector in its pro-apoptotic pathway.

file:human/BCL2L13/BCL2L13-uniprot.txt

BCL2L13 (Bcl-rambo) UniProtKB record Q9BXK5

file:human/BCL2L13/BCL2L13-notes.md

Manual BCL2L13 curation notes

Suggested Experiments

Experiment: Compare wild-type BCL2L13 with LIR-motif point mutants for LC3/GABARAP co-immunoprecipitation and for the ability to induce mitochondrial fragmentation and mitophagy (mito-Keima/mito-QC flux) in BCL2L13-null cells, including under uncoupler-induced and starvation-induced conditions.

Hypothesis: BCL2L13 acts as an LIR-dependent mitophagy receptor that recruits LC3/GABARAP to mitochondria to drive their selective autophagy.

Type: structure-function rescue and mitophagy flux assay

Experiment: Use domain-deletion and point-mutant constructs (BH motifs, LIR motif, C-terminal insertion/TM) to dissociate caspase-3 activation/apoptosis from LC3-dependent mitophagy, measuring both readouts in parallel in defined cell models.

Hypothesis: The pro-apoptotic and mitophagy-receptor activities of BCL2L13 are mechanistically separable.

Type: domain dissection with parallel apoptosis and mitophagy readouts

Deep Research

Falcon

(BCL2L13-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 21 citations 2 artifacts 2026-06-07T05:07:00.996260

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000009 The requested information is primarily found in Figures 1, 2, and 5 of the document. - **Figure 1a** provides a schematic of the Bc (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human BCL2L13 (UniProt Q9BXK5) — Functional Annotation, Biology, and Recent Research

1) Target identity verification (critical disambiguation)

The literature retrieved matches the UniProt target Q9BXK5: Bcl-2-like protein 13 (BCL2L13), also termed BCL-RAMBO / Bcl2-L-13 / MIL1, a Bcl-2 family protein that localizes to mitochondria via a C-terminal transmembrane (TM) domain and contains Bcl-2 homology motifs plus an LC3-interacting region consistent with mitophagy receptor function (murakawa2015bcl2likeprotein13 pages 1-2, kataoka2022biologicalpropertiesof pages 4-6, kataoka2022biologicalpropertiesof pages 6-8). No evidence in the retrieved set suggested a different gene/protein with the same symbol in human.

2) Key concepts and definitions (current understanding)

2.1 BCL2L13 as a mitochondrial outer-membrane (OMM) mitophagy receptor

Mitophagy is selective macroautophagy targeting mitochondria; receptor-mediated (ubiquitin-independent) mitophagy relies on OMM proteins containing LIR motifs that directly bind ATG8-family proteins (LC3/GABARAP) on forming autophagosomes (yamaguchi2016receptormediatedmitophagy. pages 4-5, kataoka2022biologicalpropertiesof pages 4-6). BCL2L13 is established as a mammalian functional homologue of yeast Atg32 that can mediate mitophagy and mitochondrial fragmentation in mammalian cells (murakawa2015bcl2likeprotein13 pages 1-2).

Mechanistically, BCL2L13 contains WXXL/I motifs, one of which functions as a LIR enabling direct binding to LC3B (murakawa2015bcl2likeprotein13 pages 1-2). CCCP-induced mitochondrial damage increases the endogenous interaction between BCL2L13 and LC3 in HEK293 cells, and BCL2L13 knockdown attenuates CCCP-induced mitochondrial fragmentation and mitophagy (yamaguchi2016receptormediatedmitophagy. pages 4-5, murakawa2015bcl2likeprotein13 pages 1-2).

2.2 Domain architecture and motifs (structure–function)

Primary and review sources converge on the following architecture:
- BH1–BH4 domains (Bcl-2 homology) (murakawa2015bcl2likeprotein13 pages 1-2, kataoka2022biologicalpropertiesof pages 4-6).
- Two WXXL/I motifs, with the second motif (~273–276 in the mouse/human-aligned region) serving as the key LIR for LC3 interaction (yamaguchi2016receptormediatedmitophagy. pages 4-5, murakawa2015bcl2likeprotein13 pages 1-2).
- In the focused review, human BCL2L13 is described as 485 aa and includes a BHNo region containing an LIR with sequence WQQI (human residues 276–279, mouse 273–276) (kataoka2022biologicalpropertiesof pages 4-6).
- A C-terminal TM domain required for mitochondrial targeting/anchoring (yamaguchi2016receptormediatedmitophagy. pages 4-5, kataoka2022biologicalpropertiesof pages 6-8).

Image-based evidence from Murakawa et al. includes a schematic of BH domains, WXXL/I motifs, and TM domain, and experimental LC3-binding data dependent on the LIR (murakawa2015bcl2likeprotein13 media a5a4456b).

2.3 Separation of functions: fragmentation vs mitophagy

A consistent theme is functional modularity:
- BH domains are required for mitochondrial fragmentation.
- The LIR/WXXI motif is required for mitophagy but not necessarily fragmentation.
This separation is explicitly described in both the primary study and the mitophagy review (yamaguchi2016receptormediatedmitophagy. pages 4-5, murakawa2015bcl2likeprotein13 pages 1-2).

2.4 Parkin-independence and relationship to canonical PINK1/Parkin mitophagy

BCL2L13 can induce mitophagy in Parkin-deficient contexts, placing it within ubiquitin-independent pathways rather than relying on the classic PINK1/Parkin ubiquitin cascade (yamaguchi2016receptormediatedmitophagy. pages 4-5, murakawa2015bcl2likeprotein13 pages 1-2).

3) Subcellular localization and cellular roles

3.1 Mitochondrial outer membrane localization

BCL2L13 is described as an outer mitochondrial membrane protein whose mitochondrial localization depends on its C-terminal TM domain (yamaguchi2016receptormediatedmitophagy. pages 4-5, murakawa2015bcl2likeprotein13 pages 1-2, kataoka2022biologicalpropertiesof pages 6-8). Murakawa et al. provide figure-level support for domain organization and mitochondrial function readouts (murakawa2015bcl2likeprotein13 media a5a4456b, murakawa2015bcl2likeprotein13 media c41d0676).

3.2 ER–mitochondria contact sites (newer localization context)

A major 2024 development is the extension of BCL2L13 function beyond canonical mitophagy receptor activity into ER–mitochondria contact site biology. Grepper et al. report BCL2L13 localization across mitochondria, ER, and mitochondria-associated membranes, and show that altering BCL2L13 affects Ca2+ handling without changing the number of ER–mitochondria contacts (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 2-4, grepper2024bcl2l13atendoplasmic pages 8-11).

4) Molecular functions, pathways, and binding partners (evidence-based)

4.1 LC3/GABARAP binding via LIR motif (core mitophagy mechanism)

BCL2L13 binds LC3 through the LIR/WXXI motif; mutation of the motif decreases LC3 interaction, and LIR integrity is required for mitophagy (murakawa2015bcl2likeprotein13 pages 1-2, murakawa2015bcl2likeprotein13 media a5a4456b). Phosphorylation near the LIR (Ser272 in mouse numbering) modulates LC3 binding and mitophagic activity (yamaguchi2016receptormediatedmitophagy. pages 4-5, kataoka2022biologicalpropertiesof pages 9-11).

4.2 ULK1 complex recruitment and initiation of mitophagy

A focused review summarizes evidence that BCL2L13 can co-immunoprecipitate with ULK1, and “appears to recruit the ULK1 complex to the MOM” to support autophagosome formation during mitophagy (kataoka2022biologicalpropertiesof pages 9-11).

4.3 Mitochondrial fragmentation/fission mechanisms (DRP1-independent vs DRP1-linked contexts)

Foundational work indicates BCL2L13 can induce fragmentation independent of DRP1/DNM1L (murakawa2015bcl2likeprotein13 pages 1-2, kataoka2022biologicalpropertiesof pages 9-11). However, recent cancer-specific work in glioblastoma indicates a distinct mechanism where BCL2L13 promotes mitochondrial fission through DNM1L Ser616 regulation, coupled to increased mitophagy flux (wang2023bcl2l13promotesmitophagy pages 1-2). This suggests context-dependent fission wiring, where BCL2L13 may either bypass DRP1 in some systems or act upstream of DRP1 activation in others (murakawa2015bcl2likeprotein13 pages 1-2, wang2023bcl2l13promotesmitophagy pages 1-2).

4.4 Additional interactors and modulators

Reviews summarize multiple reported interactions and modulators, including PGAM5, ANT, VDAC, CERS2/CERS6, LC3/GABARAP proteins, and ULK1, with PGAM5 also described as a negative regulator of BCL2L13-mediated mitophagy via dephosphorylation of a regulatory serine site (kataoka2022biologicalpropertiesof pages 11-12, kataoka2022biologicalpropertiesof pages 9-11, kataoka2022biologicalpropertiesof pages 6-8).

5) Recent developments (prioritizing 2023–2024)

5.1 Glioblastoma: BCL2L13-driven fission–mitophagy supports tumor aggressiveness (2023)

Wang et al. (Cell Death & Disease; Sep 2023; https://doi.org/10.1038/s41419-023-06112-4) report that BCL2L13 is upregulated in GBM and associates with higher grade and mesenchymal subtype. Functional knockdown reduces viability, migration, invasion, and mitophagy markers, while overexpression increases LC3B-II and mitophagy phenotypes; autophagy inhibitors reverse pro-tumor phenotypes (wang2023bcl2l13promotesmitophagy pages 2-4). In an orthotopic mouse model, reported tumor bioluminescence was approximately 55 × 10^8 vs 30 × 10^8 photons/s (control vs BCL2L13 knockdown), and Kaplan–Meier analysis indicated improved survival with knockdown (P < 0.05) (wang2023bcl2l13promotesmitophagy pages 8-11). Mechanistically, the study links BCL2L13 to DNM1L Ser616 regulation and increased mitophagy flux (wang2023bcl2l13promotesmitophagy pages 1-2).

5.2 Skeletal muscle & endurance biology: ER–mitochondria Ca2+ regulation (2024)

Grepper et al. (iScience; Aug 2024; https://doi.org/10.1016/j.isci.2024.110510) propose BCL2L13 as a regulator of ER–mitochondria Ca2+ homeostasis important for muscle function (grepper2024bcl2l13atendoplasmic pages 1-2). In bcl2l13 knockout zebrafish (n=16/group), KO animals were smaller and showed impaired locomotion and lower MO2max and Ucrit (grepper2024bcl2l13atendoplasmic pages 2-4). A striking histological statistic reported is tubular aggregates in 11% of KO fibers vs 0% in WT, consistent with disturbed SR/Ca2+ handling (grepper2024bcl2l13atendoplasmic pages 2-4). In C2C12-derived assays, Bcl2l13 knockdown reduced SR Ca2+ release and increased mitochondrial Ca2+ uptake; ER–mitochondria proximity reporters (SPLICS) and EM analyses indicate ERMC number/extent was not significantly altered, supporting a functional rather than purely structural contact-site effect (grepper2024bcl2l13atendoplasmic pages 8-11).

5.3 Diabetic kidney disease: YME1L→BCL2L13 phosphorylation enhances mitophagy to suppress tubular senescence (2024)

Luo et al. (Biological Research; Mar 2024; https://doi.org/10.1186/s40659-024-00487-0) identify BCL2L13 as a YME1L-interacting partner by LC–MS/MS and confirm interaction by co-IP in HK2 renal tubular epithelial cells; high glucose weakens this interaction and reduces phosphorylated BCL2L13 (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 15-18). YME1L overexpression increases BCL2L13 phosphorylation and strengthens BCL2L13–LC3 binding, supporting enhanced mitophagy (luo2024yme1lmediatedmitophagyprotects pages 15-18, luo2024yme1lmediatedmitophagyprotects pages 18-20). Functionally, BCL2L13 knockdown abrogates YME1L-mediated improvements in mitophagy readouts (LC3II/COX IV and LC3II/TOM20 colocalization) and anti-senescence effects (SA-β-Gal positivity, P16/P21) (luo2024yme1lmediatedmitophagyprotects pages 15-18). The study reports in vivo group sizes n=8–10 and typical cellular replicate sizes n=3–4, with standard significance thresholds (p<0.05, p<0.01, **p<0.001) (luo2024yme1lmediatedmitophagyprotects pages 20-21).

5.4 Hypoxic cardiomyocyte injury: miRNA targeting of BCL2L13 links to PI3K/AKT survival signaling (2024)

Jiang et al. (Applied Biochemistry and Biotechnology; Apr 2024; https://doi.org/10.1007/s12010-024-04931-5) show that in hypoxic AC16 human cardiomyocytes, miR-449b-5p is downregulated and BCL2L13 is validated as a direct target by dual-luciferase assays (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6). Manipulations indicate that BCL2L13 inhibition reduces hypoxia-induced viability loss, LDH release, apoptosis, and oxidative stress; BCL2L13 overexpression negates miR-449b-5p protective effects, linking BCL2L13 to injury susceptibility (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3). Reported experimental details include mimic/inhibitor concentrations and statistical analysis across three independent experiments (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6).

6) Current applications and real-world implementations

6.1 Cancer biomarker/target rationale

GBM: BCL2L13 is proposed as a candidate therapeutic target because genetic knockdown reduces tumor aggressiveness and improves survival in vivo, and autophagy inhibitors reverse BCL2L13-driven phenotypes (wang2023bcl2l13promotesmitophagy pages 2-4, wang2023bcl2l13promotesmitophagy pages 8-11). The mechanistic framing is that BCL2L13 supports protective mitophagy that tumors exploit for survival under stress (wang2023bcl2l13promotesmitophagy pages 2-4).
Renal cell carcinoma: Bioinformatic analyses and IHC indicate BCL2L13 downregulation correlates with poorer prognosis, and functional overexpression in ccRCC cells induces apoptosis and sensitizes to ABT-263 (navitoclax) (meng2021downregulationofbcl2l13 pages 7-10). While hazard ratios are not present in the retrieved excerpts, the paper explicitly positions BCL2L13 as an independent prognostic marker and mechanistically tied to mitochondrial apoptosis via SLC25A4/ANT (meng2021downregulationofbcl2l13 pages 1-2, meng2021downregulationofbcl2l13 pages 7-10).

6.2 Metabolic and organ-protection directions

DKD: The YME1L–BCL2L13 axis suggests a translational concept: enhancing receptor-mediated mitophagy via BCL2L13 phosphorylation to limit tubular senescence and preserve renal function (luo2024yme1lmediatedmitophagyprotects pages 15-18, luo2024yme1lmediatedmitophagyprotects pages 20-21).
Ischemic/hypoxic injury: miRNA-based downregulation of BCL2L13 is proposed as protective in cardiomyocyte hypoxia models, implying potential nucleic-acid therapeutics or pathway modulation strategies (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3).

7) Expert synthesis and analysis (authoritative perspectives)

Focused and mechanistic reviews emphasize that BCL2L13 is unusual among Bcl-2 family members because it participates in both mitochondrial quality control (mitophagy) and mitochondria-mediated apoptosis signaling, and that its outputs are highly context- and cell-type-dependent, likely governed by post-translational modifications (e.g., Ser272-adjacent phosphorylation), binding partners (e.g., PGAM5), and stress conditions (kataoka2022biologicalpropertiesof pages 11-12, kataoka2022biologicalpropertiesof pages 9-11, kataoka2022biologicalpropertiesof pages 6-8). The 2016 receptor-mitophagy review frames BCL2L13 as a receptor capable of driving mitophagy independently of Parkin and links its function to conserved Atg32-like design principles (LIR-mediated ATG8 binding plus mitochondrial anchoring) (yamaguchi2016receptormediatedmitophagy. pages 4-5).

8) Relevant statistics and data (recent studies)

Key quantitative/statistical items available in retrieved text:
- GBM orthotopic model (2023): tumor bioluminescence ~55 × 10^8 vs 30 × 10^8 photons/s (control vs BCL2L13 knockdown), and survival benefit P < 0.05 (wang2023bcl2l13promotesmitophagy pages 8-11).
- Skeletal muscle zebrafish KO (2024): n=16/group; tubular aggregates present in 11% of KO fibers and 0% of WT fibers (grepper2024bcl2l13atendoplasmic pages 2-4). Cellular quantification for contact sensors used n=30 cells (grepper2024bcl2l13atendoplasmic pages 8-11).
- DKD study (2024): in vivo n=8–10/group, typical in vitro n=3–4, with reported significance thresholds (p<0.05, p<0.01, p<0.001) (luo2024yme1lmediatedmitophagyprotects pages 20-21).
- Cardiomyocyte hypoxia study (2024):** experimental dosing and replicate structure reported (e.g., 50 nM mimics; 100 nM inhibitors; three independent experiments) (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6).

9) Evidence map (embedded artifact)

The following table consolidates the evidence across foundational and recent sources.

Study / source	Identity	Domains / motifs	Localization	Molecular functions	Key interactors	Pathway position	Physiological roles	Disease contexts	Recent 2023–2024 findings with citations and dates	Quantitative / statistical notes
Murakawa et al., 2015	Human/mammalian BCL2L13, also called Bcl-rambo/Bcl2-L-13; identified as a mammalian functional homologue of yeast Atg32 (murakawa2015bcl2likeprotein13 pages 1-2)	BH1–BH4 domains; two WXXL/I motifs, with the second motif at 273–276 functioning as the LC3-interacting region required for mitophagy (murakawa2015bcl2likeprotein13 pages 1-2, murakawa2015bcl2likeprotein13 media a5a4456b)	Outer mitochondrial membrane protein with C-terminal transmembrane anchor (murakawa2015bcl2likeprotein13 pages 1-2, murakawa2015bcl2likeprotein13 media a5a4456b)	Induces mitochondrial fragmentation and mitophagy; BH domains required for fragmentation, LIR required for mitophagy; fragmentation can occur independent of Drp1 and mitophagy in Parkin-deficient cells (murakawa2015bcl2likeprotein13 pages 1-2)	LC3B binding shown by GST pull-down / yeast two-hybrid; LC3 interaction enhanced after CCCP (murakawa2015bcl2likeprotein13 pages 1-2, murakawa2015bcl2likeprotein13 media a5a4456b)	Receptor-mediated, ubiquitin-independent mitophagy at the mitochondrial outer membrane; engages core autophagy machinery (murakawa2015bcl2likeprotein13 pages 1-2)	Mitochondrial quality control; rescue of mitophagy in Atg32-deficient yeast supports conserved quality-control role (murakawa2015bcl2likeprotein13 pages 1-2)	Primarily mechanistic foundational study rather than disease-focused (murakawa2015bcl2likeprotein13 pages 1-2)	Foundational primary paper establishing BCL2L13 as a mitophagy receptor and fragmentation factor, July 2015 (murakawa2015bcl2likeprotein13 pages 1-2)	Motif positions 147–150 and 273–276 defined; figure evidence shows W273A/I276A mutation weakens LC3B binding and LIR-dependent mitophagy (murakawa2015bcl2likeprotein13 media a5a4456b)
Yamaguchi et al., 2016 review	Reviews BCL2L13/Bcl-rambo as a mammalian mitophagy receptor protein (yamaguchi2016receptormediatedmitophagy. pages 4-5)	Highlights second LIR motif at residues 273–276 and adjacent Ser272 phosphorylation site regulating LC3 binding (yamaguchi2016receptormediatedmitophagy. pages 4-5)	Outer mitochondrial membrane, TM-domain anchored (yamaguchi2016receptormediatedmitophagy. pages 4-5)	Separates mitochondrial fission and mitophagy functions: BH1–4 support fission, LIR/LC3 binding specifically supports mitophagy (yamaguchi2016receptormediatedmitophagy. pages 4-5)	LC3; core autophagy factor Atg7 required in yeast rescue experiments; Parkin not required (yamaguchi2016receptormediatedmitophagy. pages 4-5)	Places BCL2L13 within receptor-mediated mitophagy, distinct from PINK1/Parkin ubiquitin-driven pathway (yamaguchi2016receptormediatedmitophagy. pages 4-5)	Mitochondrial homeostasis under stress, especially damage-induced mitophagy after CCCP (yamaguchi2016receptormediatedmitophagy. pages 4-5)	Review links mitophagy dysregulation broadly to cardiac and other diseases but not with disease-specific BCL2L13 statistics (yamaguchi2016receptormediatedmitophagy. pages 4-5)	Review synthesis published June 2016; emphasizes Ser272-dependent tuning of LC3 interaction and mitophagic activity (yamaguchi2016receptormediatedmitophagy. pages 4-5)	S272A mutant retains fragmentation but shows reduced LC3 interaction and mitophagy; knockdown attenuates CCCP-induced fragmentation/mitophagy (yamaguchi2016receptormediatedmitophagy. pages 4-5)
Kataoka, 2022 review	Human BCL2L13/BCL-RAMBO described as a BCL-2 family protein involved in apoptosis, mitochondrial fragmentation, and mitophagy (kataoka2022biologicalpropertiesof pages 4-6, kataoka2022biologicalpropertiesof pages 1-2)	Human protein 485 aa; BH1–BH4, BHNo domain, C-terminal TM domain; human LIR sequence WQQI at residues 276–279; Ser272 phosphorylation promotes mitophagy (kataoka2022biologicalpropertiesof pages 4-6, kataoka2022biologicalpropertiesof pages 9-11, kataoka2022biologicalpropertiesof pages 6-8)	Integral mitochondrial outer membrane protein; N-terminal domains exposed to cytosol; TM domain needed for mitochondrial targeting and PGAM5 binding (kataoka2022biologicalpropertiesof pages 11-12, kataoka2022biologicalpropertiesof pages 6-8)	Context-dependent apoptosis regulation, mitochondrial fragmentation, mitophagy receptor activity, and likely ULK1 recruitment to the MOM (kataoka2022biologicalpropertiesof pages 9-11, kataoka2022biologicalpropertiesof pages 6-8)	PGAM5, ULK1, LC3/GABARAP family, ANT, VDAC, CERS2/CERS6; does not co-IP with many canonical BCL-2 family partners (kataoka2022biologicalpropertiesof pages 9-11, kataoka2022biologicalpropertiesof pages 15-16, kataoka2022biologicalpropertiesof pages 6-8)	Positioned as a MOM-anchored receptor in ubiquitin-independent mitophagy; may recruit ULK1 complex and ATG8-family proteins (kataoka2022biologicalpropertiesof pages 4-6, kataoka2022biologicalpropertiesof pages 9-11)	Broad expression, relatively high in heart, skeletal muscle, pancreas; roles proposed in embryonic development, adipocyte browning, and mitochondrial quality control (kataoka2022biologicalpropertiesof pages 11-12)	Review summarizes roles across cancer, ischemia/reperfusion injury, and metabolism, but notes mechanistic complexity and cell-type dependence (kataoka2022biologicalpropertiesof pages 9-11, kataoka2022biologicalpropertiesof pages 15-16)	State-of-the-field review published December 2022 consolidating apoptosis/mitophagy/fragmentation evidence (kataoka2022biologicalpropertiesof pages 4-6, kataoka2022biologicalpropertiesof pages 9-11)	Notes apparent SDS-PAGE migration around ~85 kDa despite predicted 485 aa size; limited precise effect sizes in excerpted review text (kataoka2022biologicalpropertiesof pages 4-6)
Wang et al., 2023 GBM	Human BCL2L13 investigated in glioblastoma as an upregulated mitochondrial quality-control factor (wang2023bcl2l13promotesmitophagy pages 2-4, wang2023bcl2l13promotesmitophagy pages 1-2)	Not a motif-mapping study, but functionally linked to DNM1L Ser616-driven mitochondrial fission and mitophagy flux (wang2023bcl2l13promotesmitophagy pages 1-2)	Acts at mitochondria in GBM cells, consistent with mitophagy receptor role (wang2023bcl2l13promotesmitophagy pages 2-4)	Promotes mitophagy, proliferation, migration, and invasion; knockdown increases apoptosis and impairs tumor growth (wang2023bcl2l13promotesmitophagy pages 2-4, wang2023bcl2l13promotesmitophagy pages 8-11)	DNM1L/Drp1, BECN1, LC3B, and mitophagy/autophagy factors including NDP52, PINK1, Parkin, OPTN, BNIP3L/NIX, BNIP3 (wang2023bcl2l13promotesmitophagy pages 2-4)	Supports pro-tumor mitochondrial fission–mitophagy axis in GBM; autophagy inhibitors reverse BCL2L13-driven phenotypes (wang2023bcl2l13promotesmitophagy pages 2-4, wang2023bcl2l13promotesmitophagy pages 8-11)	In tumor cells, BCL2L13 appears to maintain mitochondrial quality control that supports survival and invasiveness rather than cell death (wang2023bcl2l13promotesmitophagy pages 2-4)	GBM: expression higher than normal brain, associated with higher grade and mesenchymal subtype; proposed biomarker/therapeutic target (wang2023bcl2l13promotesmitophagy pages 2-4, wang2023bcl2l13promotesmitophagy pages 1-2)	Key 2023 advance: Cell Death & Disease study (Sep 2023) linked BCL2L13 mechanistically to DNM1L-mediated fission and protective mitophagy in GBM (wang2023bcl2l13promotesmitophagy pages 1-2, wang2023bcl2l13promotesmitophagy pages 8-11)	Orthotopic mouse tumor bioluminescence reported ~55 × 10^8 vs ~30 × 10^8 photons/s for control vs BCL2L13 knockdown, with Kaplan–Meier survival benefit after knockdown (P < 0.05) (wang2023bcl2l13promotesmitophagy pages 8-11)
Jiang et al., 2024 cardiomyocyte hypoxia	Human BCL2L13 identified as a direct target of miR-449b-5p in AC16 cardiomyocytes under hypoxia (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	Study leverages 3'UTR targeting rather than structural mapping; prior BCL2L13 BH/TM/LIR architecture acknowledged in background (jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	Studied in human cardiomyocytes under hypoxic stress; mitochondrial/apoptotic role inferred from known biology and downstream apoptotic signaling changes (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	BCL2L13 promotes hypoxia-induced injury/apoptosis and oxidative stress in this model; suppression is protective (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	miR-449b-5p directly targets BCL2L13; downstream PI3K/AKT, Bcl-2, Bax altered (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	Positions BCL2L13 upstream of stress injury signaling in hypoxic cardiomyocytes, intersecting apoptosis and PI3K/AKT survival pathways (jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	Suggests BCL2L13 contributes to cardiomyocyte vulnerability during hypoxia/ischemic stress (jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	Cardiomyocyte hypoxia / ischemic heart disease model; therapeutic implication is inhibition of BCL2L13 via miR-449b-5p (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	Important 2024 paper (Apr 2024) showing miRNA-mediated repression of BCL2L13 ameliorates hypoxia injury in human cardiomyocytes (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6, jiang2024mir449b5pameliorateshypoxiainduced pages 1-3)	miR mimic/inhibitor doses reported (50 nM mimic, 100 nM inhibitor; co-transfection with 2 µg pcDNA3.1-BCL2L13); statistics from three independent experiments with p < 0.05 threshold, though exact fold-changes not in excerpt (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6)
Luo et al., 2024 DKD	Human/mammalian BCL2L13 implicated as a mitophagy receptor downstream of YME1L in diabetic kidney disease models (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 15-18, luo2024yme1lmediatedmitophagyprotects pages 1-2)	Focus on phosphorylation state rather than primary motif mapping; phosphorylated BCL2L13 decreases in HG/DKD and rises with YME1L overexpression (luo2024yme1lmediatedmitophagyprotects pages 15-18, luo2024yme1lmediatedmitophagyprotects pages 18-20)	Studied in HK2 renal tubular epithelial cells and diabetic mouse kidneys; mitochondrial outer membrane mitophagy receptor role is central (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 15-18)	BCL2L13 supports mitophagy that restrains renal tubular senescence; loss impairs LC3 recruitment and worsens senescence markers (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 15-18)	YME1L interacts with BCL2L13; BCL2L13-LC3 binding strengthened by YME1L-mediated phosphorylation (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 15-18)	Places BCL2L13 in a YME1L→BCL2L13 phosphorylation→LC3 binding→mitophagy pathway that protects tubules under diabetic stress (luo2024yme1lmediatedmitophagyprotects pages 15-18, luo2024yme1lmediatedmitophagyprotects pages 18-20)	Renal tubular mitochondrial quality control and anti-senescence function under high glucose (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 18-20)	Diabetic kidney disease; potential therapeutic axis through YME1L/BCL2L13-mediated mitophagy (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 20-21, luo2024yme1lmediatedmitophagyprotects pages 1-2)	Important 2024 advance (Mar 2024): Biological Research study connected BCL2L13 phosphorylation and mitophagy with protection from DKD-associated tubular senescence (luo2024yme1lmediatedmitophagyprotects pages 12-15, luo2024yme1lmediatedmitophagyprotects pages 15-18)	Cellular assays typically n = 3–4; in vivo groups n = 8–10; significance annotations reported (p < 0.05, p < 0.01, **p < 0.001), but excerpt lacks exact effect sizes for LC3II, SA-β-Gal, UACR, creatinine (luo2024yme1lmediatedmitophagyprotects pages 20-21)
Grepper et al., 2024 skeletal muscle / ER-mito contacts	BCL2L13 studied as a mammalian ER–mitochondria contact-site protein in muscle, extending beyond its classic mitophagy annotation (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 2-4)	Not primarily a motif study; relies on known BCL2L13 identity while functionally mapping ERMC localization and calcium-regulatory role (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 2-4)	Localizes to mitochondria, ER, and mitochondria-associated membranes / ER–mitochondria contact sites (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 2-4)	Regulates calcium homeostasis, muscle bioenergetics, and muscle integrity; knockdown lowers cytosolic Ca2+ release and raises mitochondrial Ca2+ uptake without increasing ERMC number (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 2-4, grepper2024bcl2l13atendoplasmic pages 8-11)	Functional links to calcium-handling machinery and mitochondrial respiratory complexes; broader background notes connection to mitophagy and apoptosis (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 4-8)	Positions BCL2L13 at ER–mitochondria signaling interfaces controlling Ca2+ flux and downstream mitochondrial metabolism in skeletal muscle (grepper2024bcl2l13atendoplasmic pages 2-4, grepper2024bcl2l13atendoplasmic pages 8-11)	Maintains skeletal muscle function and endurance-associated mitochondrial physiology (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 2-4)	Skeletal muscle dysfunction phenotype in zebrafish KO model; potentially relevant to exercise adaptation and myopathy-like states (grepper2024bcl2l13atendoplasmic pages 2-4)	Major 2024 advance (Aug 2024): iScience study expanded BCL2L13 biology from mitophagy receptor to ER–mitochondria calcium regulator in muscle (grepper2024bcl2l13atendoplasmic pages 1-2, grepper2024bcl2l13atendoplasmic pages 2-4)	n = 16 fish/group for physiology; tubular aggregates in 11% of KO fibers and 0% of WT; ERMC SPLICS assays used n = 30 cells from four transfections; EM quantification used 27 micrographs/condition; significance range p < 0.05 to ***p < 0.0001 (grepper2024bcl2l13atendoplasmic pages 2-4, grepper2024bcl2l13atendoplasmic pages 8-11, grepper2024bcl2l13atendoplasmic pages 4-8)

Table: This table summarizes core and recent evidence on human BCL2L13/Bcl-rambo, covering identity, domains, localization, molecular function, interactors, pathway role, physiology, and disease relevance. It is useful as a compact evidence map linking foundational mitophagy studies to newer 2023–2024 disease and physiology findings.

10) Limitations of available evidence in this run

Some clinically important quantities (e.g., hazard ratios for RCC prognosis; fold-change values for expression shifts; exact MO2max/Ucrit values; full p-value tables) are likely present in figures/tables of the original articles but were not included in the retrieved text excerpts for this run. Where this occurred, conclusions are stated qualitatively and tied to the study’s described statistical significance reporting (luo2024yme1lmediatedmitophagyprotects pages 20-21, grepper2024bcl2l13atendoplasmic pages 2-4).

Key URLs (publication date; journal)

Murakawa et al. 2015-07, Nature Communications: https://doi.org/10.1038/ncomms8527 (murakawa2015bcl2likeprotein13 pages 1-2)
Yamaguchi et al. 2016-06, Journal of Molecular and Cellular Cardiology (review): https://doi.org/10.1016/j.yjmcc.2016.03.010 (yamaguchi2016receptormediatedmitophagy. pages 4-5)
Kataoka 2022-12, Frontiers in Cell and Developmental Biology (review): https://doi.org/10.3389/fcell.2022.1065702 (kataoka2022biologicalpropertiesof pages 4-6)
Wang et al. 2023-09, Cell Death & Disease (GBM): https://doi.org/10.1038/s41419-023-06112-4 (wang2023bcl2l13promotesmitophagy pages 2-4)
Luo et al. 2024-03, Biological Research (DKD): https://doi.org/10.1186/s40659-024-00487-0 (luo2024yme1lmediatedmitophagyprotects pages 12-15)
Jiang et al. 2024-04, Applied Biochemistry and Biotechnology (hypoxic cardiomyocytes): https://doi.org/10.1007/s12010-024-04931-5 (jiang2024mir449b5pameliorateshypoxiainduced pages 3-6)
Grepper et al. 2024-08, iScience (muscle/ERMC Ca2+): https://doi.org/10.1016/j.isci.2024.110510 (grepper2024bcl2l13atendoplasmic pages 1-2)

References

(murakawa2015bcl2likeprotein13 pages 1-2): Tomokazu Murakawa, Osamu Yamaguchi, Ayako Hashimoto, Shungo Hikoso, Toshihiro Takeda, Takafumi Oka, Hiroki Yasui, Hiromichi Ueda, Yasuhiro Akazawa, Hiroyuki Nakayama, Manabu Taneike, Tomofumi Misaka, Shigemiki Omiya, Ajay M. Shah, Akitsugu Yamamoto, Kazuhiko Nishida, Yoshinori Ohsumi, Koji Okamoto, Yasushi Sakata, and Kinya Otsu. Bcl-2-like protein 13 is a mammalian atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nature Communications, Jul 2015. URL: https://doi.org/10.1038/ncomms8527, doi:10.1038/ncomms8527. This article has 542 citations and is from a highest quality peer-reviewed journal.
(kataoka2022biologicalpropertiesof pages 4-6): Takao Kataoka. Biological properties of the bcl-2 family protein bcl-rambo, which regulates apoptosis, mitochondrial fragmentation, and mitophagy. Frontiers in Cell and Developmental Biology, Dec 2022. URL: https://doi.org/10.3389/fcell.2022.1065702, doi:10.3389/fcell.2022.1065702. This article has 21 citations.
(kataoka2022biologicalpropertiesof pages 6-8): Takao Kataoka. Biological properties of the bcl-2 family protein bcl-rambo, which regulates apoptosis, mitochondrial fragmentation, and mitophagy. Frontiers in Cell and Developmental Biology, Dec 2022. URL: https://doi.org/10.3389/fcell.2022.1065702, doi:10.3389/fcell.2022.1065702. This article has 21 citations.
(yamaguchi2016receptormediatedmitophagy. pages 4-5): Osamu Yamaguchi, Tomokazu Murakawa, Kazuhiko Nishida, and Kinya Otsu. Receptor-mediated mitophagy. Journal of molecular and cellular cardiology, 95:50-6, Jun 2016. URL: https://doi.org/10.1016/j.yjmcc.2016.03.010, doi:10.1016/j.yjmcc.2016.03.010. This article has 96 citations and is from a domain leading peer-reviewed journal.
(murakawa2015bcl2likeprotein13 media a5a4456b): Tomokazu Murakawa, Osamu Yamaguchi, Ayako Hashimoto, Shungo Hikoso, Toshihiro Takeda, Takafumi Oka, Hiroki Yasui, Hiromichi Ueda, Yasuhiro Akazawa, Hiroyuki Nakayama, Manabu Taneike, Tomofumi Misaka, Shigemiki Omiya, Ajay M. Shah, Akitsugu Yamamoto, Kazuhiko Nishida, Yoshinori Ohsumi, Koji Okamoto, Yasushi Sakata, and Kinya Otsu. Bcl-2-like protein 13 is a mammalian atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nature Communications, Jul 2015. URL: https://doi.org/10.1038/ncomms8527, doi:10.1038/ncomms8527. This article has 542 citations and is from a highest quality peer-reviewed journal.
(murakawa2015bcl2likeprotein13 media c41d0676): Tomokazu Murakawa, Osamu Yamaguchi, Ayako Hashimoto, Shungo Hikoso, Toshihiro Takeda, Takafumi Oka, Hiroki Yasui, Hiromichi Ueda, Yasuhiro Akazawa, Hiroyuki Nakayama, Manabu Taneike, Tomofumi Misaka, Shigemiki Omiya, Ajay M. Shah, Akitsugu Yamamoto, Kazuhiko Nishida, Yoshinori Ohsumi, Koji Okamoto, Yasushi Sakata, and Kinya Otsu. Bcl-2-like protein 13 is a mammalian atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nature Communications, Jul 2015. URL: https://doi.org/10.1038/ncomms8527, doi:10.1038/ncomms8527. This article has 542 citations and is from a highest quality peer-reviewed journal.
(grepper2024bcl2l13atendoplasmic pages 1-2): Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K.F. Aguettaz, Mauricio Castro-Sepulveda, Dorian V. Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, and Francesca Amati. Bcl2l13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function. iScience, 27:110510, Aug 2024. URL: https://doi.org/10.1016/j.isci.2024.110510, doi:10.1016/j.isci.2024.110510. This article has 10 citations and is from a peer-reviewed journal.
(grepper2024bcl2l13atendoplasmic pages 2-4): Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K.F. Aguettaz, Mauricio Castro-Sepulveda, Dorian V. Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, and Francesca Amati. Bcl2l13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function. iScience, 27:110510, Aug 2024. URL: https://doi.org/10.1016/j.isci.2024.110510, doi:10.1016/j.isci.2024.110510. This article has 10 citations and is from a peer-reviewed journal.
(grepper2024bcl2l13atendoplasmic pages 8-11): Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K.F. Aguettaz, Mauricio Castro-Sepulveda, Dorian V. Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, and Francesca Amati. Bcl2l13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function. iScience, 27:110510, Aug 2024. URL: https://doi.org/10.1016/j.isci.2024.110510, doi:10.1016/j.isci.2024.110510. This article has 10 citations and is from a peer-reviewed journal.
(kataoka2022biologicalpropertiesof pages 9-11): Takao Kataoka. Biological properties of the bcl-2 family protein bcl-rambo, which regulates apoptosis, mitochondrial fragmentation, and mitophagy. Frontiers in Cell and Developmental Biology, Dec 2022. URL: https://doi.org/10.3389/fcell.2022.1065702, doi:10.3389/fcell.2022.1065702. This article has 21 citations.
(wang2023bcl2l13promotesmitophagy pages 1-2): Jiwei Wang, Anbin Chen, Zhiwei Xue, Junzhi Liu, Ying He, Guowei Liu, Zhimin Zhao, Wenjie Li, Qing Zhang, Anjing Chen, Jian Wang, Xingang Li, Xinyu Wang, and Bin Huang. Bcl2l13 promotes mitophagy through dnm1l-mediated mitochondrial fission in glioblastoma. Cell Death & Disease, Sep 2023. URL: https://doi.org/10.1038/s41419-023-06112-4, doi:10.1038/s41419-023-06112-4. This article has 41 citations and is from a peer-reviewed journal.
(kataoka2022biologicalpropertiesof pages 11-12): Takao Kataoka. Biological properties of the bcl-2 family protein bcl-rambo, which regulates apoptosis, mitochondrial fragmentation, and mitophagy. Frontiers in Cell and Developmental Biology, Dec 2022. URL: https://doi.org/10.3389/fcell.2022.1065702, doi:10.3389/fcell.2022.1065702. This article has 21 citations.
(wang2023bcl2l13promotesmitophagy pages 2-4): Jiwei Wang, Anbin Chen, Zhiwei Xue, Junzhi Liu, Ying He, Guowei Liu, Zhimin Zhao, Wenjie Li, Qing Zhang, Anjing Chen, Jian Wang, Xingang Li, Xinyu Wang, and Bin Huang. Bcl2l13 promotes mitophagy through dnm1l-mediated mitochondrial fission in glioblastoma. Cell Death & Disease, Sep 2023. URL: https://doi.org/10.1038/s41419-023-06112-4, doi:10.1038/s41419-023-06112-4. This article has 41 citations and is from a peer-reviewed journal.
(wang2023bcl2l13promotesmitophagy pages 8-11): Jiwei Wang, Anbin Chen, Zhiwei Xue, Junzhi Liu, Ying He, Guowei Liu, Zhimin Zhao, Wenjie Li, Qing Zhang, Anjing Chen, Jian Wang, Xingang Li, Xinyu Wang, and Bin Huang. Bcl2l13 promotes mitophagy through dnm1l-mediated mitochondrial fission in glioblastoma. Cell Death & Disease, Sep 2023. URL: https://doi.org/10.1038/s41419-023-06112-4, doi:10.1038/s41419-023-06112-4. This article has 41 citations and is from a peer-reviewed journal.
(luo2024yme1lmediatedmitophagyprotects pages 12-15): Yuanyuan Luo, Lingxiao Zhang, Ning Su, Lerong Liu, and Tongfeng Zhao. Yme1l-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions. Biological Research, Mar 2024. URL: https://doi.org/10.1186/s40659-024-00487-0, doi:10.1186/s40659-024-00487-0. This article has 16 citations and is from a peer-reviewed journal.
(luo2024yme1lmediatedmitophagyprotects pages 15-18): Yuanyuan Luo, Lingxiao Zhang, Ning Su, Lerong Liu, and Tongfeng Zhao. Yme1l-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions. Biological Research, Mar 2024. URL: https://doi.org/10.1186/s40659-024-00487-0, doi:10.1186/s40659-024-00487-0. This article has 16 citations and is from a peer-reviewed journal.
(luo2024yme1lmediatedmitophagyprotects pages 18-20): Yuanyuan Luo, Lingxiao Zhang, Ning Su, Lerong Liu, and Tongfeng Zhao. Yme1l-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions. Biological Research, Mar 2024. URL: https://doi.org/10.1186/s40659-024-00487-0, doi:10.1186/s40659-024-00487-0. This article has 16 citations and is from a peer-reviewed journal.
(luo2024yme1lmediatedmitophagyprotects pages 20-21): Yuanyuan Luo, Lingxiao Zhang, Ning Su, Lerong Liu, and Tongfeng Zhao. Yme1l-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions. Biological Research, Mar 2024. URL: https://doi.org/10.1186/s40659-024-00487-0, doi:10.1186/s40659-024-00487-0. This article has 16 citations and is from a peer-reviewed journal.
(jiang2024mir449b5pameliorateshypoxiainduced pages 3-6): Yang Jiang, Zeyan Liu, Li Ye, Jinglin Cheng, and Jun Wan. Mir-449b-5p ameliorates hypoxia-induced cardiomyocyte injury through activating pi3k/akt pathway by targeting bcl2l13. Applied biochemistry and biotechnology, Apr 2024. URL: https://doi.org/10.1007/s12010-024-04931-5, doi:10.1007/s12010-024-04931-5. This article has 0 citations and is from a peer-reviewed journal.
(jiang2024mir449b5pameliorateshypoxiainduced pages 1-3): Yang Jiang, Zeyan Liu, Li Ye, Jinglin Cheng, and Jun Wan. Mir-449b-5p ameliorates hypoxia-induced cardiomyocyte injury through activating pi3k/akt pathway by targeting bcl2l13. Applied biochemistry and biotechnology, Apr 2024. URL: https://doi.org/10.1007/s12010-024-04931-5, doi:10.1007/s12010-024-04931-5. This article has 0 citations and is from a peer-reviewed journal.
(meng2021downregulationofbcl2l13 pages 7-10): Fei Meng, Luojin Zhang, Mingjun Zhang, Kaiqin Ye, Wei Guo, Yu Liu, Wulin Yang, Zhimin Zhai, Hongzhi Wang, Jun Xiao, and Haiming Dai. Down-regulation of bcl2l13 renders poor prognosis in clear cell and papillary renal cell carcinoma. Cancer Cell International, Jun 2021. URL: https://doi.org/10.1186/s12935-021-02039-y, doi:10.1186/s12935-021-02039-y. This article has 7 citations and is from a peer-reviewed journal.
(meng2021downregulationofbcl2l13 pages 1-2): Fei Meng, Luojin Zhang, Mingjun Zhang, Kaiqin Ye, Wei Guo, Yu Liu, Wulin Yang, Zhimin Zhai, Hongzhi Wang, Jun Xiao, and Haiming Dai. Down-regulation of bcl2l13 renders poor prognosis in clear cell and papillary renal cell carcinoma. Cancer Cell International, Jun 2021. URL: https://doi.org/10.1186/s12935-021-02039-y, doi:10.1186/s12935-021-02039-y. This article has 7 citations and is from a peer-reviewed journal.
(kataoka2022biologicalpropertiesof pages 1-2): Takao Kataoka. Biological properties of the bcl-2 family protein bcl-rambo, which regulates apoptosis, mitochondrial fragmentation, and mitophagy. Frontiers in Cell and Developmental Biology, Dec 2022. URL: https://doi.org/10.3389/fcell.2022.1065702, doi:10.3389/fcell.2022.1065702. This article has 21 citations.
(kataoka2022biologicalpropertiesof pages 15-16): Takao Kataoka. Biological properties of the bcl-2 family protein bcl-rambo, which regulates apoptosis, mitochondrial fragmentation, and mitophagy. Frontiers in Cell and Developmental Biology, Dec 2022. URL: https://doi.org/10.3389/fcell.2022.1065702, doi:10.3389/fcell.2022.1065702. This article has 21 citations.
(luo2024yme1lmediatedmitophagyprotects pages 1-2): Yuanyuan Luo, Lingxiao Zhang, Ning Su, Lerong Liu, and Tongfeng Zhao. Yme1l-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions. Biological Research, Mar 2024. URL: https://doi.org/10.1186/s40659-024-00487-0, doi:10.1186/s40659-024-00487-0. This article has 16 citations and is from a peer-reviewed journal.
(grepper2024bcl2l13atendoplasmic pages 4-8): Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K.F. Aguettaz, Mauricio Castro-Sepulveda, Dorian V. Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, and Francesca Amati. Bcl2l13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function. iScience, 27:110510, Aug 2024. URL: https://doi.org/10.1016/j.isci.2024.110510, doi:10.1016/j.isci.2024.110510. This article has 10 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

kataoka2022biologicalpropertiesof pages 4-6
kataoka2022biologicalpropertiesof pages 9-11
kataoka2022biologicalpropertiesof pages 11-12
kataoka2022biologicalpropertiesof pages 6-8
kataoka2022biologicalpropertiesof pages 1-2
kataoka2022biologicalpropertiesof pages 15-16
https://doi.org/10.1038/s41419-023-06112-4
https://doi.org/10.1016/j.isci.2024.110510
https://doi.org/10.1186/s40659-024-00487-0
https://doi.org/10.1007/s12010-024-04931-5
https://doi.org/10.1038/ncomms8527
https://doi.org/10.1016/j.yjmcc.2016.03.010
https://doi.org/10.3389/fcell.2022.1065702
https://doi.org/10.1038/ncomms8527,
https://doi.org/10.3389/fcell.2022.1065702,
https://doi.org/10.1016/j.yjmcc.2016.03.010,
https://doi.org/10.1016/j.isci.2024.110510,
https://doi.org/10.1038/s41419-023-06112-4,
https://doi.org/10.1186/s40659-024-00487-0,
https://doi.org/10.1007/s12010-024-04931-5,
https://doi.org/10.1186/s12935-021-02039-y,

📚 Additional Documentation

Notes

(BCL2L13-notes.md)

BCL2L13 (Bcl-rambo / Mil1) curation notes

UniProt: Q9BXK5 (B2L13_HUMAN). Synonyms: Bcl-rambo, Mil1, BCL2L13, ORFNames=CD003.
485 aa (canonical isoform 2 displayed, Q9BXK5-1). Single-pass tail-anchored membrane protein
(FT TRANSMEM 460..480). Contains BH4 (14..30), BH3 (100..116), BH1 (147..157), BH2 (193..206)
motifs, plus a unique ~250 aa insertion with two tandem repeats (A, B) preceding the C-terminal
transmembrane anchor.

Core function synthesis

BCL2L13/Bcl-rambo is a mitochondrial outer-membrane (tail-anchored) BCL-2-family protein. The two
best-established, distinct activities reported in the literature are:

Mitophagy receptor — BCL2L13 is the mammalian functional homolog of yeast Atg32. It carries a
WXXL-type LIR (LC3-interacting region) and binds LC3/GABARAP-family proteins to recruit the
autophagy machinery to mitochondria, inducing mitochondrial fragmentation and mitophagy. The
foundational study (Murakawa et al., Nat Commun 2015, PMID:26471991) is NOT among the GOA-cited
references and is NOT cached in this repo, so it cannot be used for verbatim supporting_text;
however, the UniProt IntAct interaction table directly records BCL2L13 binding to the human Atg8
ortholog GABARAPL2 (P60520), consistent with the LIR-dependent receptor model.
[file:human/BCL2L13/BCL2L13-uniprot.txt "Q9BXK5; P60520: GABARAPL2; NbExp=4; IntAct=EBI-747430, EBI-720116;"]
UniProt/Ensembl GOA also carries GO:0000423 mitophagy (IEA:Ensembl) and GO:0007005 mitochondrion
organization (IEA:Ensembl), reflecting this role, though these specific terms are not in the
seeded existing_annotations set.
[file:human/BCL2L13/BCL2L13-uniprot.txt "GO:0000423; P:mitophagy; IEA:Ensembl."]
Apoptosis (original characterization) — Bcl-rambo was first described as a pro-apoptotic
BCL-2 homolog whose cell-death activity is induced by its membrane-anchored C-terminal domain
(the unique insertion + TM), NOT by its BH motifs, and is blocked by caspase inhibitors/IAPs but
not by Bcl-xL. Notably it does NOT heterodimerize with other BCL-2-family members.
PMID:11262395
PMID:11262395
PMID:11262395

The apoptosis function is the basis of the GOA NAS annotations (PMID:11262395): apoptotic process
(GO:0006915), mitochondrion (GO:0005739), cysteine-type endopeptidase activator activity involved
in apoptotic process (GO:0008656, i.e. caspase-3 activation), and membrane (GO:0016020, IDA).
UniProt FUNCTION: "May promote the activation of caspase-3 and apoptosis."
[file:human/BCL2L13/BCL2L13-uniprot.txt "FUNCTION: May promote the activation of caspase-3 and apoptosis."]

The original overexpression-driven apoptosis phenotype is the historical view; the more recent and
mechanistically distinct mitophagy-receptor role (Atg32 homolog) is now regarded as a central,
conserved function. Distinguishing CORE (mitophagy receptor / mitochondrial fragmentation) from the
context-dependent apoptosis annotations is the main curation task.

Legionella SidF (apoptosis inhibition by pathogen)

Legionella pneumophila effector SidF specifically interacts with and neutralizes BNIP3 and Bcl-rambo
to inhibit host macrophage apoptosis, confirming Bcl-rambo as a genuine pro-death host protein and a
pathogen target. UniProt IntAct records Q9BXK5-sidF (Q5ZSD5, Xeno).
PMID:17360363
PMID:17360363
The seeded GO:0005515 protein binding IPI from PMID:17360363 corresponds to this SidF interaction;
as bare protein binding it is uninformative and is marked over-annotated.

Localization

UniProt: Isoform 2 (canonical, Q9BXK5-1): Mitochondrion membrane; Single-pass membrane protein;
Nucleus. Isoform 1 (Q9BXK5-2, a short 201-aa form): Nucleus.
[file:human/BCL2L13/BCL2L13-uniprot.txt "SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion membrane"]
Mitochondrial (outer) membrane is the core functional location. The Nucleus localization is reported
(largely for the truncated isoform 1, which lacks the TM anchor) and is secondary; isoform 1
(Q9BXK5-2) ends at residue 201 (VSP_000526/VSP_000527) and is nuclear.

Protein binding annotations

Many GO:0005515 protein binding IPI annotations derive from high-throughput interactome papers
(16189514, 25416956, 25910212, 26871637, 28514442, 32296183, 32814053, 33961781) plus the specific
SidF study (17360363). The UniProt IntAct table is dominated by membrane-protein partners (many
single-pass TM proteins, e.g. PLN, MAL, PLP1, VAMP3/4, syntaxins), consistent with a
membrane-embedded tail-anchored protein; most are not functionally informative. "protein binding"
is uninformative and marked over-annotated. The functionally meaningful interaction is with the
Atg8-family protein GABARAPL2 (mitophagy receptor activity), but that is recorded as an IntAct hit,
not among the seeded protein-binding annotations with a cached PMID.

Key existing annotation classification summary

CORE (mitophagy receptor / mitochondrial fragmentation): mitochondrion (GO:0005739) localization,
membrane (better as mitochondrial outer membrane). NOTE: the defining mitophagy MF/BP terms are not
in the seeded set (they exist in UniProt GOA as IEA: GO:0000423 mitophagy, GO:0007005 mitochondrion
organization) — proposed as new/expanded annotation.

SECONDARY / NON-CORE: apoptotic process, regulation of apoptotic process, caspase-3 activator
activity (GO:0008656), nucleus localization.

OVER-ANNOTATED / UNINFORMATIVE: protein binding (GO:0005515) — all instances.

Caveat

The strongest evidence for the mitophagy-receptor / Atg32-homolog function (Murakawa et al. 2015)
is not in the cached publications, so verbatim supporting_text for that function is drawn only from
the UniProt record (GABARAPL2 IntAct interaction; GO:0000423 mitophagy IEA) and is reflected in the
description, core_functions, and proposed_new_terms rather than asserted from an inaccessible PMID.

Falcon deep research findings (2026-06-07)

PMID correction: the foundational Murakawa et al. Nat Commun 2015 mitophagy/Atg32 paper is
PMID:26146385 (DOI 10.1038/ncomms8527), not PMID:26471991 as guessed earlier in these notes.
Verified via PubMed ID conversion (DOI->PMID) and metadata lookup. None of the new papers below are
cached in publications/, so they are added to the review as statement-only findings (no
verbatim supporting_text).

CONFIRMS (now with a citable primary PMID): BCL2L13 is the mammalian Atg32 homolog; it binds LC3
via a WXXI/LIR motif and induces both mitochondrial fragmentation and mitophagy. BH domains drive
fragmentation; the WXXI/LIR motif drives mitophagy. Fragmentation occurs without DRP1/DNM1L, and
mitophagy proceeds in Parkin-deficient cells (ubiquitin-independent, Parkin-independent).
PMID:26146385 (Murakawa 2015, Nat Commun). This grounds the existing
description/core_functions that were previously inferred only from UniProt.
NEW (mechanism): Phosphorylation regulates the receptor. A Ser site adjacent to the LIR
(Ser272, mouse numbering; human LIR is WQQI at ~276-279) tunes LC3 binding and mitophagic activity;
PGAM5 acts as a negative regulator by dephosphorylating BCL2L13, and BCL2L13 has been reported to
recruit the ULK1 complex to the mitochondrial outer membrane to initiate autophagosome formation.
Additional reported interactors/modulators include ULK1, PGAM5, ANT (SLC25A4), VDAC, and CERS2/CERS6.
Source: Kataoka 2022 review PMID:36589739 (review-level; mechanistic detail, treat as provisional
where based only on review synthesis).
NEW (localization/process): Beyond the mitochondrial outer membrane, BCL2L13 also localizes at
ER-mitochondria contact sites / mitochondria-associated membranes (MAMs) and regulates
ER-mitochondria Ca2+ homeostasis in skeletal muscle. Knockdown alters cytosolic Ca2+ release and
mitochondrial Ca2+ uptake without changing the NUMBER of ER-mito contacts (a functional, not
structural, contact-site effect); Bcl2l13-KO zebrafish show impaired muscle structure/function and
decreased mitochondrial complex activity. PMID:39175772 (Grepper 2024, iScience). This is a genuinely new functional context
(Ca2+ homeostasis at MAMs) not in the existing review.
NEW (disease / context-dependent fission wiring): In glioblastoma, BCL2L13 is upregulated and
promotes mitochondrial fission and high mitophagy flux by targeting DNM1L at Ser616, supporting tumor
proliferation/invasion. This is notable because it is DNM1L(DRP1)-DEPENDENT, in apparent contrast to
the DRP1-independent fragmentation seen by Murakawa 2015 - i.e., context-dependent fission wiring.
PMID:37660127 (Wang 2023, Cell Death Dis). Do NOT use this to override the DRP1-independent core
claim; both are valid in their respective contexts.
NEW (interactor/pathway, disease): In diabetic kidney disease, BCL2L13 was identified by LC-MS/MS as
an interacting partner of the inner-membrane protease YME1L; YME1L promotes BCL2L13 phosphorylation,
strengthening BCL2L13-LC3 binding and mitophagy to restrain renal tubular senescence.
PMID:38494498 (Luo 2024, Biol Res). New YME1L interactor.
NEW (disease, prognosis): In clear-cell and papillary renal cell carcinoma, BCL2L13 is downregulated
and lower expression correlates with poorer prognosis (independent of grade); BCL2L13 is positively
correlated with and acts through SLC25A4/ANT in its pro-apoptotic pathway. PMID:34193180 (Meng 2021, Cancer Cell Int). Contrasts with the pro-survival/oncogenic role in GBM,
reinforcing strong context/tissue dependence.
PROVISIONAL / not used to change annotations: a 2024 study reports miR-449b-5p directly targets the
BCL2L13 3'UTR in hypoxic AC16 cardiomyocytes, with BCL2L13 suppression being protective via PI3K/AKT
(Jiang 2024, Appl Biochem Biotechnol, DOI 10.1007/s12010-024-04931-5; 0 citations at report time).
Low-confidence/peripheral to GO core function; kept in notes only, no PMID added to the review.

Curation impact: existing annotation actions are unchanged. The new primary references (Murakawa 2015,
Kataoka 2022, Grepper 2024, Wang 2023, Luo 2024, Meng 2021) are added to references: as statement-only
findings. Murakawa 2015 now provides a citable primary basis for the mitophagy-receptor core function.
Grepper 2024 (ER-mito contact / Ca2+) and the YME1L/SLC25A4 interactors are the main genuinely-new
biology; added suggested questions/experiments accordingly.

Pn Notes

(BCL2L13-pn-notes.md)

BCL2L13 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9BXK5
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/BCL2L13/BCL2L13-ai-review.yaml
AIGR review HTML: present - genes/human/BCL2L13/BCL2L13-ai-review.html
Gene notes: present - genes/human/BCL2L13/BCL2L13-notes.md
GOA TSV: present - genes/human/BCL2L13/BCL2L13-goa.tsv
UniProt record: present - genes/human/BCL2L13/BCL2L13-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/BCL2L13.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/BCL2L13.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/BCL2L13/BCL2L13-deep-research-falcon.md

AIGR Review Snapshot

Description: BCL2L13 (Bcl-rambo, Mil1) is a tail-anchored mitochondrial outer-membrane protein of the BCL-2 family that contains all four BCL-2 homology motifs (BH1-BH4) plus a unique ~250-residue insertion with tandem repeats preceding its C-terminal transmembrane anchor. It is the mammalian functional homolog of the yeast mitophagy receptor Atg32: through an LC3-interacting region it binds Atg8-family proteins (LC3/GABARAP, including GABARAPL2) to recruit the autophagy machinery to mitochondria, promoting mitochondrial fragmentation and selective autophagy of mitochondria (mitophagy) independently of the canonical DRP1 fission machinery. BCL2L13 was originally described as a pro-apoptotic BCL-2 homolog whose cell-death activity, which can promote caspase-3 activation, is conferred by its membrane-anchored C-terminal region rather than its BH motifs; unlike most BCL-2-family members it does not heterodimerize with other family members. It is broadly expressed (notably in heart, placenta, pancreas and skeletal muscle) and is targeted by the Legionella pneumophila effector SidF, which neutralizes it to block host apoptosis. A short nuclear-localized splice isoform lacking the transmembrane anchor also exists.
Existing/core annotation action counts: ACCEPT: 6; KEEP_AS_NON_CORE: 5; MARK_AS_OVER_ANNOTATED: 11; NEW: 2

PN Consistency Summary

Consistency: Consistent. PN (selective-autophagy/mitophagy receptor, Atg32 homolog binding LC3/ATG8 via LIR, induces fragmentation + Parkin-independent mitophagy), the review, notes and Falcon deep research all agree (PMID:26146385 Murakawa 2015; UniProt GABARAPL2 IntAct; PMID:36589739). PN Notes match the review description verbatim in substance.
PN story / NEW pressure: PN projects GO:0000423 mitophagy as new_to_goa. The review notes UniProt/Ensembl GOA already carries GO:0000423 (IEA), but it is absent from the seeded existing_annotations — so adding the process is warranted (mild discrepancy: "new_to_goa" vs already-IEA-in-UniProt). The stronger NEW pressure is the MF: as with BNIP3L, the review proposes a new term "mitophagy receptor activity" stating the seeded set lacks any mitophagy MF. GO:0140580 "mitochondrion autophagosome adaptor activity" already exists and exactly captures the LIR-tethering activity — so the MF should be ADD GO:0140580, not a brand-new term. Conclusion: process partly captured (IEA), MF capturable by an existing real term that both PN and the review missed.
Evidence alignment: PN cites the Murakawa Nat Commun mitophagy paper (=PMID:26146385) and a selective-autophagy ATG8/LIR review — both align with the review's references. Strong overlap. Deep research adds DRP1-dependent (GBM, PMID:37660127) vs DRP1-independent (Murakawa) context and MAM/Ca2+ role (PMID:39175772), none contradicting the mitophagy core.
Verdict: Consistent; mitophagy process correctly added (note it is already IEA in UniProt GOA). Key finding: the review's proposed NEW "mitophagy receptor activity" duplicates existing GO:0140580. Recommended edits: [YAML][REF] replace the BCL2L13 proposed_new_term with existing GO:0140580 mitochondrion autophagosome adaptor activity (add as core MF, supported by PMID:26146385); [MAP] note GO:0000423 is already UniProt-IEA, so goa_status is closer to "already_in_goa" than "new_to_goa".

Full Consistency Review

UniProt: Q9BXK5 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE
PN placement: Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Mitophagy ; PN-node mapping: Mitophagy type → mapped/ok_for_propagation GO:0000423 mitophagy (goa_status=new_to_goa); group/class/branch → no_mapping.
Consistency: Consistent. PN (selective-autophagy/mitophagy receptor, Atg32 homolog binding LC3/ATG8 via LIR, induces fragmentation + Parkin-independent mitophagy), the review, notes and Falcon deep research all agree (PMID:26146385 Murakawa 2015; UniProt GABARAPL2 IntAct; PMID:36589739). PN Notes match the review description verbatim in substance.
PN story / NEW pressure: PN projects GO:0000423 mitophagy as new_to_goa. The review notes UniProt/Ensembl GOA already carries GO:0000423 (IEA), but it is absent from the seeded existing_annotations — so adding the process is warranted (mild discrepancy: "new_to_goa" vs already-IEA-in-UniProt). The stronger NEW pressure is the MF: as with BNIP3L, the review proposes a new term "mitophagy receptor activity" stating the seeded set lacks any mitophagy MF. GO:0140580 "mitochondrion autophagosome adaptor activity" already exists and exactly captures the LIR-tethering activity — so the MF should be ADD GO:0140580, not a brand-new term. Conclusion: process partly captured (IEA), MF capturable by an existing real term that both PN and the review missed.
Mapping strategy: Mitophagy type → GO:0000423 projection is appropriate for BCL2L13 (well-supported Atg32-homolog receptor). The shared-node projection is sound; this gene strengthens (does not over-broaden) the node, unlike rejected-broader precedents.
Evidence alignment: PN cites the Murakawa Nat Commun mitophagy paper (=PMID:26146385) and a selective-autophagy ATG8/LIR review — both align with the review's references. Strong overlap. Deep research adds DRP1-dependent (GBM, PMID:37660127) vs DRP1-independent (Murakawa) context and MAM/Ca2+ role (PMID:39175772), none contradicting the mitophagy core.
Verdict: Consistent; mitophagy process correctly added (note it is already IEA in UniProt GOA). Key finding: the review's proposed NEW "mitophagy receptor activity" duplicates existing GO:0140580. Recommended edits: [YAML][REF] replace the BCL2L13 proposed_new_term with existing GO:0140580 mitochondrion autophagosome adaptor activity (add as core MF, supported by PMID:26146385); [MAP] note GO:0000423 is already UniProt-IEA, so goa_status is closer to "already_in_goa" than "new_to_goa".
2026-06-18 follow-up: Implemented the high-confidence YAML edits: added GO:0140580 mitochondrion autophagosome adaptor activity and GO:0000423 mitophagy as NEW recommendations, updated the core MF, and removed the duplicate mitophagy-receptor NTR block. Mapping goa_status cleanup remains separate.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/BCL2L13/BCL2L13-ai-review.yaml
PN workbook rows: 1

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Mitophagy

UniProt: Q9BXK5
In branches: ALP
Notes: Receptor for selective autophagy. Atg32 homologue binds to LC3/ATG8 and induces mitochondrial fragmentation and mitophagy in an Parkin independent manner.
PN references (titles):
- Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors - ScienceDirect
- Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Mitophagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000423 mitophagy]
  rationale: This PN path denotes selective-autophagy receptors for mitochondrial cargo. The source category is a mechanistic sub-role within mitophagy, so propagation rather than exact equivalence is the correct scope.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0000423 mitophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Mitophagy

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q9BXK5
gene_symbol: BCL2L13
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'BCL2L13 (Bcl-rambo, Mil1) is a tail-anchored mitochondrial outer-membrane protein of the BCL-2 family that contains all four BCL-2 homology motifs (BH1-BH4) plus a unique ~250-residue insertion with tandem repeats preceding its C-terminal transmembrane anchor. It is the mammalian functional homolog of the yeast mitophagy receptor Atg32: through an LC3-interacting region it binds Atg8-family proteins (LC3/GABARAP, including GABARAPL2) to recruit the autophagy machinery to mitochondria, promoting mitochondrial fragmentation and selective autophagy of mitochondria (mitophagy) independently of the canonical DRP1 fission machinery. BCL2L13 was originally described as a pro-apoptotic BCL-2 homolog whose cell-death activity, which can promote caspase-3 activation, is conferred by its membrane-anchored C-terminal region rather than its BH motifs; unlike most BCL-2-family members it does not heterodimerize with other family members. It is broadly expressed (notably in heart, placenta, pancreas and skeletal muscle) and is targeted by the Legionella pneumophila effector SidF, which neutralizes it to block host apoptosis. A short nuclear-localized splice isoform lacking the transmembrane anchor also exists.'
alternative_products:
- name: '2'
  id: Q9BXK5-1
- name: '1'
  id: Q9BXK5-2
  sequence_note: VSP_000526, VSP_000527
- name: '3'
  id: Q9BXK5-4
  sequence_note: VSP_046931
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: BCL2L13 is a mitochondrial protein that acts at the mitochondrion (mitophagy receptor and pro-apoptotic activity at the mitochondrial outer membrane).
    action: ACCEPT
    reason: Mitochondrial localization/activity is strongly and consistently supported; the mitochondrion is the principal functional compartment.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: Bcl-rambo was localized to mitochondria
      reference_section_type: ABSTRACT
    - reference_id: file:human/BCL2L13/BCL2L13-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: BCL2L13 is a single-pass tail-anchored membrane protein; generic membrane localization is correct but uninformative relative to the specific mitochondrial membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane term is subsumed by the more specific and well-supported mitochondrial (outer) membrane localization.
    supported_by:
    - reference_id: file:human/BCL2L13/BCL2L13-uniprot.txt
      supporting_text: Single-pass membrane protein
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A nuclear localization is reported in UniProt, largely for the truncated isoform 1 that lacks the transmembrane anchor; it is secondary to the mitochondrial role.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is documented (especially for the short nuclear isoform) but is not the functional compartment for the conserved mitophagy/mitochondrial activities.
    supported_by:
    - reference_id: file:human/BCL2L13/BCL2L13-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Nucleus'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: BCL2L13/Bcl-rambo can promote apoptosis (originally described as a pro-apoptotic BCL-2 homolog), an InterPro-based transfer consistent with the experimental literature.
    action: KEEP_AS_NON_CORE
    reason: A pro-apoptotic capacity is genuine but context/overexpression-dependent and secondary to the conserved mitophagy-receptor function.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs
      reference_section_type: ABSTRACT
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: BCL2L13 is anchored in the mitochondrial membrane (outer membrane), consistent with its tail-anchor and UniProt subcellular location.
    action: ACCEPT
    reason: Well-supported core localization; the mitochondrial membrane is where BCL2L13 acts.
    supported_by:
    - reference_id: file:human/BCL2L13/BCL2L13-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: As a BCL-2-family protein with pro-apoptotic activity, BCL2L13 participates in regulation of apoptosis; an InterPro-based transfer consistent with the literature.
    action: KEEP_AS_NON_CORE
    reason: Supported by the apoptosis literature but context-dependent and secondary to the mitophagy-receptor function.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a proteome-scale interaction map does not identify an interpretable BCL2L13 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17360363
  qualifier: enables
  review:
    summary: This protein-binding annotation reflects the specific interaction of Bcl-rambo with the Legionella effector SidF (which neutralizes it to block host apoptosis); as bare protein binding it is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying SidF interaction is meaningful and confirms Bcl-rambo as a pro-death host target, but the generic protein binding term does not capture this; no specific GO binding term for a bacterial effector applies.
    supported_by:
    - reference_id: PMID:17360363
      supporting_text: SidF contributes to apoptosis resistance in L. pneumophila-infected cells by specifically interacting with and neutralizing the effects of BNIP3 and Bcl-rambo, two proapoptotic members of Bcl2 protein family.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a proteome-scale interactome map is not functionally specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a disease-interactome perturbation study is not functionally specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: High-throughput alternative-splicing interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a large-scale splicing-interactome study is not functionally specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a large-scale interactome study is not functionally specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a reference binary interactome map is not functionally specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: High-throughput neurodegenerative-disease interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a disease-interactome study is not functionally specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a cell-specific interactome remodeling study is not functionally specific.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Orthology-based transfer of mitochondrial activity, consistent with the well-supported mitochondrial localization/function of BCL2L13.
    action: ACCEPT
    reason: Consistent with the core mitochondrial compartment where BCL2L13 acts.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: Bcl-rambo was localized to mitochondria
      reference_section_type: ABSTRACT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based mitochondrial localization, consistent with the literature.
    action: ACCEPT
    reason: Directly supported core localization.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: Bcl-rambo was localized to mitochondria
      reference_section_type: ABSTRACT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteome localization, consistent with BCL2L13 being a mitochondrial protein.
    action: ACCEPT
    reason: Consistent with the well-supported core mitochondrial localization.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: mitochondrial proteome
      reference_section_type: TITLE
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:11262395
  qualifier: involved_in
  review:
    summary: The founding Bcl-rambo study reports that overexpression induces caspase-dependent apoptosis, providing the basis for the apoptotic-process annotation.
    action: KEEP_AS_NON_CORE
    reason: A pro-apoptotic role is supported but is overexpression-driven and context-dependent; secondary to the conserved mitophagy-receptor function.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs
      reference_section_type: ABSTRACT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:11262395
  qualifier: located_in
  review:
    summary: The founding study localized Bcl-rambo to mitochondria.
    action: ACCEPT
    reason: Directly supported core localization.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: Bcl-rambo was localized to mitochondria
      reference_section_type: ABSTRACT
- term:
    id: GO:0008656
    label: cysteine-type endopeptidase activator activity involved in apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:11262395
  qualifier: enables
  review:
    summary: BCL2L13-induced apoptosis is caspase-dependent (blocked by caspase inhibitors/IAPs), and UniProt states it may promote caspase-3 activation; this caspase-activator annotation captures a contextual pro-apoptotic effect rather than a direct, conserved molecular function.
    action: KEEP_AS_NON_CORE
    reason: The caspase-3 activation is indirect/context-dependent (overexpression-driven apoptosis) and is not the conserved core molecular function (mitophagy-receptor activity); retained as a non-core apoptosis-related annotation.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs
      reference_section_type: ABSTRACT
    - reference_id: file:human/BCL2L13/BCL2L13-uniprot.txt
      supporting_text: May promote the activation of caspase-3 and apoptosis.
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:11262395
  qualifier: located_in
  review:
    summary: Bcl-rambo's cell-death activity maps to its membrane-anchored C-terminal domain; generic membrane localization is correct but uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by the specific mitochondrial (outer) membrane localization.
    supported_by:
    - reference_id: PMID:11262395
      supporting_text: the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain
      reference_section_type: ABSTRACT
- term:
    id: GO:0140580
    label: mitochondrion autophagosome adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:26146385
  qualifier: enables
  review:
    summary: BCL2L13/Bcl2-L-13 is an outer-mitochondrial-membrane mitophagy receptor that binds LC3 through its WXXI/LIR motif and recruits autophagy machinery to mitochondria.
    action: NEW
    reason: The PN-guided review identified that the YAML's proposed "mitophagy receptor activity" request is already covered by GO:0140580. This existing MF should be added instead of requesting a new term.
    supported_by:
    - reference_id: PMID:26146385
      supporting_text: Bcl2-L-13 binds to LC3 through the WXXI motif and induces mitochondrial fragmentation and mitophagy
      reference_section_type: ABSTRACT
- term:
    id: GO:0000423
    label: mitophagy
  evidence_type: IMP
  original_reference_id: PMID:26146385
  qualifier: involved_in
  review:
    summary: BCL2L13 promotes selective autophagy of mitochondria, and knockdown attenuates damage-induced mitochondrial fragmentation and mitophagy.
    action: NEW
    reason: The review already treats mitophagy as the core biological process, but the seeded existing_annotations lacked a manual recommendation for the BP term. This adds the existing GO process term with primary evidence.
    supported_by:
    - reference_id: PMID:26146385
      supporting_text: Knockdown of Bcl2-L-13 attenuates mitochondrial damage-induced fragmentation and mitophagy
      reference_section_type: ABSTRACT
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:11262395
  title: Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique
    C-terminal extension.
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:17360363
  title: Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death
    members of the Bcl2 protein family.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:26146385
  title: Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy
    and mitochondrial fragmentation.
  full_text_unavailable: true
  findings:
  - statement: BCL2L13 is the mammalian functional homolog of yeast Atg32; it binds
      LC3 through a WXXI/LIR motif and induces both mitochondrial fragmentation and
      mitophagy. The BH domains mediate fragmentation while the WXXI motif facilitates
      mitophagy.
  - statement: BCL2L13 induces mitochondrial fragmentation in the absence of DRP1/DNM1L
      and induces mitophagy in Parkin-deficient cells, placing it in a ubiquitin-independent,
      Parkin-independent receptor-mediated mitophagy pathway, and it can rescue mitophagy
      in Atg32-deficient yeast.
- id: PMID:36589739
  title: Biological properties of the BCL-2 family protein BCL-RAMBO, which regulates
    apoptosis, mitochondrial fragmentation, and mitophagy.
  full_text_unavailable: true
  findings:
  - statement: BCL-RAMBO/BCL2L13 is an integral mitochondrial outer-membrane protein
      with BH1-BH4 domains, a BHNo region containing the LC3-interacting region (human
      LIR WQQI), and a C-terminal transmembrane anchor; it functions as a mitophagy
      receptor recruiting ATG8-family proteins (LC3/GABARAP) via the LIR motif.
  - statement: Phosphorylation near the LIR (Ser272 in mouse numbering) tunes LC3
      binding and mitophagic activity; PGAM5 acts as a negative regulator by dephosphorylating
      BCL2L13, and BCL2L13 is reported to recruit the ULK1 complex to the mitochondrial
      outer membrane to initiate mitophagy.
- id: PMID:39175772
  title: BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium
    homeostasis to maintain skeletal muscle function.
  full_text_unavailable: true
  findings:
  - statement: BCL2L13 localizes to mitochondria, ER, and mitochondria-associated
      membranes (ER-mitochondria contact sites) and regulates ER-mitochondria calcium
      homeostasis; its knockdown alters cytosolic calcium release and mitochondrial
      calcium uptake without changing the number of ER-mitochondria contact sites,
      indicating a functional rather than structural contact-site role.
  - statement: Loss of Bcl2l13 in zebrafish impairs skeletal muscle structure and
      function and decreases mitochondrial complex activity, supporting a physiological
      role in muscle bioenergetics and calcium handling.
- id: PMID:37660127
  title: BCL2L13 promotes mitophagy through DNM1L-mediated mitochondrial fission in
    glioblastoma.
  full_text_unavailable: true
  findings:
  - statement: In glioblastoma, BCL2L13 is upregulated and promotes mitochondrial
      fission and high mitophagy flux by targeting DNM1L (DRP1) at the Ser616 site,
      promoting tumor proliferation and invasion; this DNM1L-dependent mechanism is
      context-specific and contrasts with DRP1-independent fragmentation reported elsewhere.
- id: PMID:38494498
  title: YME1L-mediated mitophagy protects renal tubular cells against cellular senescence
    under diabetic conditions.
  full_text_unavailable: true
  findings:
  - statement: BCL2L13 was identified by LC-MS/MS as an interacting partner of the
      inner mitochondrial membrane protease YME1L; YME1L promotes phosphorylation
      of BCL2L13, strengthening BCL2L13-LC3 binding and enhancing mitophagy to restrain
      renal tubular epithelial cell senescence in diabetic kidney disease models.
- id: PMID:34193180
  title: Down-regulation of BCL2L13 renders poor prognosis in clear cell and papillary
    renal cell carcinoma.
  full_text_unavailable: true
  findings:
  - statement: BCL2L13 expression is decreased in clear-cell and papillary renal cell
      carcinoma and lower expression correlates with poorer prognosis independently
      of tumor grade; BCL2L13 positively correlates with SLC25A4 (ANT), implicated
      as a downstream effector in its pro-apoptotic pathway.
- id: file:human/BCL2L13/BCL2L13-uniprot.txt
  title: BCL2L13 (Bcl-rambo) UniProtKB record Q9BXK5
  findings: []
- id: file:human/BCL2L13/BCL2L13-notes.md
  title: Manual BCL2L13 curation notes
  findings: []
core_functions:
- description: BCL2L13/Bcl-rambo functions as a mitophagy receptor at the mitochondrial outer membrane. As the mammalian functional homolog of yeast Atg32, it binds Atg8-family proteins (LC3/GABARAP, including GABARAPL2) via an LC3-interacting region to recruit autophagy machinery to mitochondria, promoting mitochondrial fragmentation and selective autophagy of mitochondria.
  molecular_function:
    id: GO:0140580
    label: mitochondrion autophagosome adaptor activity
  directly_involved_in:
  - id: GO:0000423
    label: mitophagy
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: file:human/BCL2L13/BCL2L13-uniprot.txt
    supporting_text: 'Q9BXK5; P60520: GABARAPL2; NbExp=4; IntAct=EBI-747430, EBI-720116;'
    reference_section_type: DATABASE_ENTRY
  - reference_id: file:human/BCL2L13/BCL2L13-uniprot.txt
    supporting_text: GO:0000423; P:mitophagy; IEA:Ensembl.
    reference_section_type: DATABASE_ENTRY
- description: BCL2L13 has a context-dependent pro-apoptotic activity. Originally characterized as a BCL-2 homolog whose overexpression induces caspase-dependent apoptosis via its membrane-anchored C-terminal region (not its BH motifs), it can promote caspase-3 activation and does not heterodimerize with other BCL-2-family members; it is a target of the Legionella effector SidF.
  directly_involved_in:
  - id: GO:0006915
    label: apoptotic process
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: PMID:11262395
    supporting_text: its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs
    reference_section_type: ABSTRACT
  - reference_id: PMID:11262395
    supporting_text: the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: In normal physiology, is BCL2L13's predominant role the Atg32-like mitophagy-receptor function, the pro-apoptotic function, or are these separable activities engaged in different cell types or stress conditions?
  experts:
  - Murakawa T
  - Otsu K
- question: Does BCL2L13-mediated mitochondrial fragmentation occur independently of the canonical DRP1 fission machinery, and how is the LIR-dependent LC3 binding regulated?
  experts:
  - Murakawa T
  - Otsu K
- question: Is BCL2L13's localization to ER-mitochondria contact sites (mitochondria-associated membranes) and its regulation of ER-mitochondria Ca2+ flux a distinct function from its mitophagy-receptor activity, or are the two mechanistically coupled?
  experts:
  - Amati F
  - Grepper D
- question: How is the choice between DRP1-independent fragmentation (Murakawa) and DNM1L/DRP1-Ser616-dependent fission (glioblastoma) determined, and which cellular contexts favor each, given the opposing tissue-dependent roles of BCL2L13 (pro-survival in GBM vs tumor-suppressive in renal cell carcinoma)?
suggested_experiments:
- hypothesis: BCL2L13 acts as an LIR-dependent mitophagy receptor that recruits LC3/GABARAP to mitochondria to drive their selective autophagy.
  description: Compare wild-type BCL2L13 with LIR-motif point mutants for LC3/GABARAP co-immunoprecipitation and for the ability to induce mitochondrial fragmentation and mitophagy (mito-Keima/mito-QC flux) in BCL2L13-null cells, including under uncoupler-induced and starvation-induced conditions.
  experiment_type: structure-function rescue and mitophagy flux assay
- hypothesis: The pro-apoptotic and mitophagy-receptor activities of BCL2L13 are mechanistically separable.
  description: Use domain-deletion and point-mutant constructs (BH motifs, LIR motif, C-terminal insertion/TM) to dissociate caspase-3 activation/apoptosis from LC3-dependent mitophagy, measuring both readouts in parallel in defined cell models.
  experiment_type: domain dissection with parallel apoptosis and mitophagy readouts

BCL2L13

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human BCL2L13 (UniProt Q9BXK5) — Functional Annotation, Biology, and Recent Research

1) Target identity verification (critical disambiguation)

2) Key concepts and definitions (current understanding)

2.1 BCL2L13 as a mitochondrial outer-membrane (OMM) mitophagy receptor

2.2 Domain architecture and motifs (structure–function)

2.3 Separation of functions: fragmentation vs mitophagy

2.4 Parkin-independence and relationship to canonical PINK1/Parkin mitophagy

3) Subcellular localization and cellular roles

3.1 Mitochondrial outer membrane localization

3.2 ER–mitochondria contact sites (newer localization context)

4) Molecular functions, pathways, and binding partners (evidence-based)

4.1 LC3/GABARAP binding via LIR motif (core mitophagy mechanism)

4.2 ULK1 complex recruitment and initiation of mitophagy

4.3 Mitochondrial fragmentation/fission mechanisms (DRP1-independent vs DRP1-linked contexts)

4.4 Additional interactors and modulators

5) Recent developments (prioritizing 2023–2024)

5.1 Glioblastoma: BCL2L13-driven fission–mitophagy supports tumor aggressiveness (2023)

5.2 Skeletal muscle & endurance biology: ER–mitochondria Ca2+ regulation (2024)

5.3 Diabetic kidney disease: YME1L→BCL2L13 phosphorylation enhances mitophagy to suppress tubular senescence (2024)

5.4 Hypoxic cardiomyocyte injury: miRNA targeting of BCL2L13 links to PI3K/AKT survival signaling (2024)

6) Current applications and real-world implementations

6.1 Cancer biomarker/target rationale

6.2 Metabolic and organ-protection directions

7) Expert synthesis and analysis (authoritative perspectives)

8) Relevant statistics and data (recent studies)

9) Evidence map (embedded artifact)

10) Limitations of available evidence in this run

Key URLs (publication date; journal)

Artifacts

Citations

📚 Additional Documentation

Notes

BCL2L13 (Bcl-rambo / Mil1) curation notes

Core function synthesis

Legionella SidF (apoptosis inhibition by pathogen)

Localization

Protein binding annotations

Key existing annotation classification summary

Caveat

Falcon deep research findings (2026-06-07)

Pn Notes

BCL2L13 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Mitophagy

Projected GO annotations (1)

Note

📄 View Raw YAML