Mitophagy

Mitophagy is the selective macroautophagy of mitochondria. In animals, damaged or unwanted mitochondria are marked on their outer membrane and captured by phagophores decorated with Atg8-family proteins (LC3 and GABARAP in mammals, LGG-1 in nematodes). Two kinds of mark are used. In the ubiquitin-dependent route, the kinase PINK1 accumulates on the outer membrane of depolarized or import-defective mitochondria and phosphorylates ubiquitin and the ubiquitin-like domain of the RBR E3 ligase Parkin at Ser65. Activated Parkin builds ubiquitin chains on outer-membrane proteins, and in mammals these chains are read by soluble ubiquitin-binding receptors such as optineurin and NDP52, which also bind LC3/GABARAP and recruit the autophagy initiation machinery. In the receptor-mediated route, integral outer-membrane proteins bind Atg8-family proteins directly through LC3-interacting regions. BNIP3 and NIX (BNIP3L) act in hypoxia-induced and developmental mitophagy, such as mitochondrial clearance in maturing reticulocytes, and FUNDC1 acts in hypoxia-induced mitophagy. These receptors are conserved in nematodes, where the BNIP3/NIX ortholog DCT-1 acts in stress-induced somatic mitophagy together with PINK-1 and the Parkin ortholog PDR-1, and the FUNDC1 ortholog FNDC-1 acts in hypoxia-reoxygenation mitophagy. Nematodes also have lineage-specific components. Paternal mitochondria and membranous organelles in the C. elegans embryo are cleared by the nematode-specific receptor ALLO-1 (allophagy), and in worm muscle the FIS1-family proteins FIS-1 and FIS-2 act at a late step to complete orderly disposal of fission-derived mitochondrial fragments.

MODULE:mitophagyDRAFTCONCRETEBiological Processmodules/mitophagy.yaml

mitophagyGO:0000423

PMID:24751536

PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity.

PINK1 phosphorylates ubiquitin at Ser65, the same position it phosphorylates in the Parkin ubiquitin-like domain, and phospho-ubiquitin activates Parkin.

Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain.

PMID:26266977

The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.

In human cells, NDP52 and optineurin are the main receptors for PINK1/Parkin-mediated mitophagy.

Using genome editing to knock out five autophagy receptors, we find that two previously linked to xenophagy, NDP52 and Optineurin, are the primary receptors for PINK1/Parkin-mediated mitophagy.

PMID:25896323

Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

DCT-1 is a key mediator of stress-induced mitophagy in C. elegans, and mitophagy is coupled to mitochondrial biogenesis through SKN-1.

We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans.

PMID:25896323

Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

Impaired mitophagy triggers SKN-1 retrograde signalling that raises both mitochondrial biogenesis and DCT-1 expression.

triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression

PMID:33734301

Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process.

Secondary statement of the earlier primary finding that severe heat stress induces mitophagy in muscle that depends on DCT-1, PINK-1 and PDR-1, and that DCT-1/NIX and FUNDC1 are the known worm mitophagy receptors.

a severe and prolonged HS induces a DCT-1

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

Nascent mitophagosomes are seen in worm muscle as LGG-1 spots on the mitochondrial surface. They are absent in pink-1 mutants.

pink-1 single and pink-1 fis-1 fis-2 triple mutant animals had no colocalizing spots, as expected for a complete block of mitophagy

PMID:31153831

Ubiquitination is required for the initial removal of paternal organelles in C. elegans.

Paternal mitochondria are removed by two temporally distinct routes, an early ubiquitin-dependent route and a later FNDC-1-dependent route.

there are at least two different mechanisms for targeting paternal mitochondria for elimination: the first involving ubiquitination and a second involving a mitochondrial associated autophagy receptor, fndc-1

PMID:27145933

FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions.

Human FUNDC1 also acts at ER-mitochondria contact sites as a DRP1 adaptor for hypoxic fission. That role is outside this module and belongs with mitochondrial dynamics.

Taken together, these findings reveal that FUNDC1 is not only a novel MAM protein that acts as an adaptor for DRP1 during the mitochondrial fission process, but also involved in hypoxia‐induced mitophagy.

file:genes/worm/pink-1/pink-1-ai-review.yaml

worm pink-1 gene review

Core function: protein serine/threonine kinase activity in mitophagy at mitochondria. The ubiquitin and Parkin Ser65 phosphorylation mechanism is carried over from mammalian PINK1.

file:genes/human/PINK1/PINK1-ai-review.yaml

human PINK1 gene review

Core function: damage-sensing ubiquitin and Parkin kinase (protein serine/threonine kinase activity) in mitophagy at the mitochondrial outer membrane.

file:genes/worm/pdr-1/pdr-1-ai-review.yaml

worm pdr-1 gene review

Core function: RBR-family ubiquitin protein ligase activity in mitophagy, in the cytosol and on the mitochondrial outer membrane.

file:genes/human/PRKN/PRKN-ai-review.yaml

human PRKN gene review

Core function: PINK1-activated RBR E3 ubiquitin ligase for damaged mitochondria (ubiquitin protein ligase activity in mitophagy).

file:genes/human/OPTN/OPTN-ai-review.yaml

human OPTN gene review

Core function: receptor for PINK1/Parkin-dependent mitophagy that binds polyubiquitin through its UBAN domain and LC3/GABARAP through its LIR (protein-macromolecule adaptor activity in type 2 mitophagy).

file:genes/human/CALCOCO2/CALCOCO2-ai-review.yaml

human CALCOCO2 gene review

Core function: selective-autophagy cargo adaptor in xenophagy and mitophagy.

file:genes/worm/dct-1/dct-1-ai-review.yaml

worm dct-1 gene review

Core function: mitochondrion autophagosome adaptor activity (GO:0140580) in mitophagy at the mitochondrial outer membrane. The review records PINK-1-dependent ubiquitination of DCT-1 at Lys-26 under oxidative stress, from the full text of PMID:25896323.

file:genes/human/BNIP3/BNIP3-ai-review.yaml

human BNIP3 gene review

Core functions: mitochondrion autophagosome adaptor activity in mitophagy, an ER-autophagosome adaptor role in reticulophagy, and hypoxia-induced promotion of macroautophagy. Pro-death activity is not treated as core.

file:genes/human/BNIP3L/BNIP3L-ai-review.yaml

human BNIP3L gene review

Core function: NIX is a mitophagy receptor at the mitochondrial outer membrane (mitochondrion autophagosome adaptor activity), essential for mitochondrial elimination during reticulocyte maturation.

file:genes/worm/fndc-1/fndc-1-ai-review.yaml

worm fndc-1 gene review

Core function: mitochondrion autophagosome adaptor activity (GO:0140580) in mitophagy at the mitochondrial outer membrane.

file:genes/human/FUNDC1/FUNDC1-ai-review.yaml

human FUNDC1 gene review

Core functions: ubiquitin-independent mitophagy receptor (mitochondrion autophagosome adaptor activity), and a separate DRP1 adaptor role at ER-mitochondria contact sites in hypoxic fission.

file:genes/worm/allo-1/allo-1-ai-review.yaml

worm allo-1 gene review

Core function: autophagy cargo adaptor activity in allophagy of paternal mitochondria and membranous organelles. Isoforms differ in cargo preference, and ALLO-1 also recruits the ULK complex.

file:genes/worm/lgg-1/lgg-1-ai-review.yaml

worm lgg-1 gene review

Core function: PE-conjugated Atg8-family modifier on autophagosome membranes. The review accepts its mitophagy annotations and its direct binding to the ALLO-1 and SQST-1 receptors.

file:genes/human/GABARAP/GABARAP-ai-review.yaml

human GABARAP gene review

Core function: Atg8-family protein conjugated to phosphatidylethanolamine on autophagic membranes (phosphatidylethanolamine binding), in autophagosome assembly, maturation and mitophagy.

file:genes/human/MAP1LC3B/MAP1LC3B-ai-review.yaml

human MAP1LC3B gene review

Core function: Atg8-family protein conjugated to phospholipid on the autophagosome membrane (phosphatidylethanolamine binding), in autophagosome assembly and mitophagy.

file:genes/worm/sqst-1/sqst-1-ai-review.yaml

worm sqst-1 gene review

Keeps the IBA mitophagy annotation as non-core because a role for SQST-1 in worm mitophagy has not been shown. SQST-1 is therefore not a member of this module.

file:projects/CAEEL_MITOPHAGY.md

C. elegans Mitophagy and Mitochondrial Quality Control project page

Project page listing the worm mitophagy and mitochondrial dynamics gene reviews from which this module was first built.

Boundary. This module covers the selective capture of mitochondria by the autophagy machinery in animals. It starts at the marking of a mitochondrion (PINK1/Parkin ubiquitin signalling, or an outer-membrane receptor) and ends at receptor engagement of Atg8-family proteins on the phagophore and, in nematodes, the FIS-1/FIS-2-dependent completion of disposal. Building the autophagosome (ULK1 initiation, PI3KC3-C1 PI3P synthesis, ATG9, ATG2/WIPI, and the ATG7/ATG3/ATG16L1 lipidation cascade) is the subject of MODULE:metazoan_autophagosome_biogenesis and is not re-modeled here; the Atg8-family proteins appear only in their role as the docking site that receptors bind. Autophagosome-lysosome fusion and degradation are also downstream and outside this boundary. The phagophore-ER contact that supplies lipid for phagophore growth is MODULE:phagophore_organelle_contact_site. The ER-mitochondria contact (MAM), where worm FIS-1 and human FUNDC1 also act, is a separate structure from the phagophore-ER contact. Taxon. The context is Eumetazoa. PAINT places the IBD statements for the PINK1 node (PTN001121970) and the BNIP3/NIX node (PTN001032684) at Eumetazoa, and the Parkin mitophagy node (PTN000188399) at Bilateria. The FUN14 and Atg8 family nodes are eukaryotic, so those two roles are older than the module. Mitophagy also occurs in fungi and plants, but there it uses different receptors (for example yeast Atg32) and no PINK1 or Parkin, so the boundary modeled here does not hold outside animals. Worm and human are the representatives. Drosophila Pink1 and parkin are classic genetic models of the ubiquitin route but have no gene review here, so they are not listed as representatives. Lineage differences. The ubiquitin-reading soluble receptors optineurin and NDP52 (CALCOCO2) are vertebrate proteins; no clear C. elegans ortholog of either has been identified, and which protein reads PDR-1-made ubiquitin in worms is unknown. ALLO-1 and the FIS-1/FIS-2 late disposal step are known only in C. elegans. In worms, PINK-1 and PDR-1 are placed in mitophagy by genetics (reporters, epistasis, LGG-1 colocalization) and by PDR-1 E3 ligase activity toward other substrates; ubiquitin Ser65 phosphorylation and phosphorylation-driven PDR-1 activation are carried over from the human and insect biochemistry. Fission. Stress-induced mitophagy in worm muscle uses MFF-dependent DRP-1 fission upstream of the FIS-1/FIS-2 step. The fission machinery itself is in MODULE:mitochondrial_dynamics. Fission is not required for every route: oxidative-stress-induced neuronal mitophagy in worms is drp-1-independent but partly pink-1-dependent (PMID:35916724). Fission is therefore recorded as context, not as a required part. Human FUNDC1 has a second, separate role as a DRP1 adaptor at ER-mitochondria contacts during hypoxia (PMID:27145933); that fission role is out of scope here. Members left out. SQSTM1/p62 (worm SQST-1) is excluded: the worm review keeps the mitophagy annotation as non-core with no worm evidence, its demonstrated worm role is aggrephagy, and in human cells it is not one of the primary PINK1/Parkin mitophagy receptors (PMID:26266977). TAX1BP1 and NBR1 are minor receptors in that assay and are not modeled. TBK1 (worm IKKE-1) phosphorylates optineurin, NDP52 and ALLO-1 and is described in the receptor annotons, not modeled as its own member. Human FIS1 has no gene review here and is not modeled; its role in mammalian mitophagy is recorded only in notes. BNIP3 and NIX pro-death (BH3-like) activity and their ER-phagy role are not part of this module. MIRO1 is a PINK1 and Parkin substrate but is not a mitophagy receptor. The E2 enzymes UBC-18 and UBC-16 that ubiquitinate paternal membranous organelles, and the transcriptional regulators SKN-1, ATFS-1 and DAF-16, are context, not machinery. ATFS-1 and the mitochondrial unfolded protein response are in MODULE:mitochondrial_upr. Accessions. LGG-1 is Q09490, the accession used by the lgg-1 review and UniProt. The project page gives a different accession. PANTHER. The PINK1 subfamily (PTHR22972:SF7), the BNIP3/NIX family (PTHR15186) and the Atg8 family (PTHR10969) contain both the worm and human representatives. No family term is given for Parkin, because the UniProt PANTHER cross-reference for human PRKN (PTHR10677) differs from the PAINT family that holds the Parkin node (PTHR11685), or for FUNDC1, because the FUN14 family (PTHR21346) also contains FUNDC2 and yeast Fun14, which are not mitophagy receptors. Negative regulation. Part 5 adds human FBXL4, the outer-membrane SCF substrate adaptor that constitutively degrades BNIP3 and NIX and so keeps basal receptor-mediated mitophagy low (completed FBXL4 review). It is a regulatory part, not a required step, and has only a human representative; no nematode counterpart has been assessed. The PPTC7 adaptor that links BNIP3/NIX to FBXL4 has no gene review and is not modelled. PANTHER PTHR13318:SF152 is taken from the human UniProt cross-reference.

10Nodes

5Parts

1Variant Sets

4Variants

11Annotons

5Connections

Derived QC

Recommended-field compliance

78.9% recommended fields populated

knowledge_gaps[0].provenance[0] · reference_section_type (0/1)
knowledge_gaps[1] · boundary (0/1)
knowledge_gaps[1].provenance[0] · reference_section_type (0/1)
knowledge_gaps[2].provenance[0] · reference_section_type (0/1)

Module deep research

✗ none found

No MODULE:mitophagy deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

atg8_capture → fis1_disposal [NOT_CHECKED]

Function consistency and core coverage

18 gene-function check(s) reflected in core functions · 0 conflict(s) · 5 evidence or coverage gap(s) (24 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
pink1_kinase	PINK1 (human) UniProtKB:Q9BXM7 Family Representative	protein serine/threonine kinase activity GO:0004674	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pink1_kinase	PINK-1 (worm) UniProtKB:Q09298 Family Representative	protein serine/threonine kinase activity GO:0004674	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
parkin_ligase	PRKN (human) UniProtKB:O60260 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
parkin_ligase	PDR-1 (worm) UniProtKB:Q9XUS3 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
optn_receptor	OPTN (human) UniProtKB:Q96CV9 Gene	protein-macromolecule adaptor activity GO:0030674	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ndp52_receptor	CALCOCO2/NDP52 (human) UniProtKB:Q13137 Gene	autophagy cargo adaptor activity GO:0160247	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bnip3_adaptor	BNIP3 (human) UniProtKB:Q12983 Family Representative	mitochondrion autophagosome adaptor activity GO:0140580	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bnip3_adaptor	BNIP3L/NIX (human) UniProtKB:O60238 Family Representative	mitochondrion autophagosome adaptor activity GO:0140580	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bnip3_adaptor	DCT-1 (worm) UniProtKB:Q09969 Family Representative	mitochondrion autophagosome adaptor activity GO:0140580	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fundc1_adaptor	FUNDC1 (human) UniProtKB:Q8IVP5 Family Representative	mitochondrion autophagosome adaptor activity GO:0140580	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fundc1_adaptor	FNDC-1 (worm) UniProtKB:Q22252 Family Representative	mitochondrion autophagosome adaptor activity GO:0140580	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
allo1_adaptor	ALLO-1 (worm) UniProtKB:Q9U389 Gene	autophagy cargo adaptor activity GO:0160247	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atg8_family	GABARAP (human) UniProtKB:O95166 Family Representative	phosphatidylethanolamine binding GO:0008429	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atg8_family	MAP1LC3B (human) UniProtKB:Q9GZQ8 Family Representative	phosphatidylethanolamine binding GO:0008429	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atg8_family	LGG-1 (worm) UniProtKB:Q09490 Family Representative	phosphatidylethanolamine binding GO:0008429	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fis1_adaptor	FIS-1 (worm) UniProtKB:Q20291 Gene	molecular adaptor activity GO:0060090	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fis2_adaptor	FIS-2 (worm) UniProtKB:Q6AHP8 Gene	molecular adaptor activity GO:0060090	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fbxl4_receptor_degradation	FBXL4 (human) UniProtKB:Q9UKA2 Family Representative	ubiquitin-like ligase-substrate adaptor activity GO:1990756	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pink1_kinase	PINK1 mitochondrial serine/threonine kinases PANTHER:PTHR22972:SF7 Family	protein serine/threonine kinase activity GO:0004674	Family Review Missing No supported structured family review is available for PANTHER:PTHR22972:SF7.
parkin_ligase	Parkin RBR E3 ubiquitin ligases Family	ubiquitin protein ligase activity GO:0061630	Family Id Missing The family has no identifier linking it to a curated family review.
bnip3_adaptor	BNIP3/NIX family PANTHER:PTHR15186 Family	mitochondrion autophagosome adaptor activity GO:0140580	Family Supported Family review supports GO:0140580 FAMILY_WIDE. The LIR is intact in every member examined across all three characterized subfamilies, and the activity is experimentally demonstrated in BNIP3 (SF4), NIX (SF3) and, as a mitophagy receptor, DCT-1 (SF5). It is currently propagated only within SF4; a family-node IBD (PTN001032684) would correct the omission for NIX, DCT-1 and fly BNIP3.
fundc1_adaptor	FUNDC1 mitophagy receptors (FUN14 domain) Family	mitochondrion autophagosome adaptor activity GO:0140580	Family Id Missing The family has no identifier linking it to a curated family review.
atg8_family	Atg8 family (LC3 and GABARAP subfamilies) PANTHER:PTHR10969 Family	phosphatidylethanolamine binding GO:0008429	Family Review Missing No supported structured family review is available for PANTHER:PTHR10969.
fbxl4_receptor_degradation	F-box/LRR-repeat protein 4 PANTHER:PTHR13318:SF152 Family	ubiquitin-like ligase-substrate adaptor activity GO:1990756	Family Review Missing No supported structured family review is available for PANTHER:PTHR13318:SF152.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

fbxl4_receptor_turnover ⊣ bnip3_nix_receptor [input]
fbxl4_receptor_turnover is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (18/18 grounded genes reviewed)

12 complete review(s) · 10 with deep research · 0 missing review · 8 reviewed but lacking deep research

Gene	Review	Complete	Deep research
allo-1 Q9U389	✓	✓	✗
BNIP3 Q12983	✓	177/179	✗
BNIP3L O60238	✓	✓	✓
CALCOCO2 Q13137	✓	43/44	✓
dct-1 Q09969	✓	✓	✓
FBXL4 Q9UKA2	✓	28/29	✓
fis-1 Q20291	✓	✓	✓
fis-2 Q6AHP8	✓	✓	✓
fndc-1 Q22252	✓	✓	✓
FUNDC1 Q8IVP5	✓	45/46	✗
GABARAP O95166	✓	✓	✗
lgg-1 Q09490	✓	48/49	✓
MAP1LC3B Q9GZQ8	✓	✓	✗
OPTN Q96CV9	✓	✓	✗
pdr-1 Q9XUS3	✓	✓	✓
pink-1 Q09298	✓	✓	✓
PINK1 Q9BXM7	✓	✓	✗
PRKN O60260	✓	426/427	✗

Tree

MitophagyBiological Processmitophagy

Parts
1. 1. ubiquitin-dependent marking of damaged mitochondria
2. PINK1/Parkin ubiquitin signalling on damaged mitochondriaSignaling Pathwaypink1_parkin_marking
  
  Annotons
  - PINK1 ubiquitin and Parkin kinase Family: PINK1 mitochondrial serine/threonine kinases
  - Parkin RBR E3 ubiquitin ligase Family: Parkin RBR E3 ubiquitin ligases
3. 2. receptor recognition of marked mitochondria
4. Mitophagy receptor recognitionBiological Processmitophagy_receptor_recognition
  
  Variants
  1. Mitophagy receptors by type and lineage by receptor type (ubiquitin-reading soluble receptor or integral outer-membrane receptor) and sequence lineage (One Or More)
    
    Optineurin and NDP52 ubiquitin-binding mitophagy receptors (vertebrate)Biological Processubiquitin_binding_receptors
    
    Annotons
    
    Optineurin ubiquitin-binding mitophagy receptor Gene Product: OPTN (human)
    
    NDP52 (CALCOCO2) ubiquitin-binding mitophagy receptor Gene Product: CALCOCO2/NDP52 (human)
    
    BNIP3/NIX-family outer-membrane mitophagy receptorBiological Processbnip3_nix_receptor
    
    Annotons
    
    BNIP3/NIX mitochondrion-autophagosome adaptor Family: BNIP3/NIX family
    
    FUNDC1-family ubiquitin-independent mitophagy receptorBiological Processfundc1_receptor
    
    Annotons
    
    FUNDC1 mitochondrion-autophagosome adaptor Family: FUNDC1 mitophagy receptors (FUN14 domain)
    
    ALLO-1 allophagy receptor for paternal organelles (nematode)Biological Processallo1_receptor
    
    Annotons
    
    ALLO-1 cargo adaptor Gene Product: ALLO-1 (worm)
5. 3. receptor capture by Atg8-family proteins on the phagophore
6. Atg8-family docking of mitophagy receptors on the phagophoreBiological Processatg8_capture
  
  Annotons
  - Phagophore-anchored Atg8-family protein Family: Atg8 family (LC3 and GABARAP subfamilies)
7. 4. completion of orderly disposal of fission-derived mitochondrial fragments (nematode)
8. FIS-1/FIS-2-dependent disposal of damaged mitochondria (nematode)Biological Processfis1_disposal
  
  Annotons
  - FIS-1 outer-membrane disposal adaptor Gene Product: FIS-1 (worm)
  - FIS-2 outer-membrane disposal adaptor Gene Product: FIS-2 (worm)
9. 5. basal restraint of receptor-mediated mitophagy (vertebrate)
10. SCF-FBXL4 degrades BNIP3 and NIX to restrain basal mitophagyRegulatory Stepfbxl4_receptor_turnover
  
  Annotons
  - FBXL4: SCF substrate adaptor for BNIP3/NIX turnover Family: F-box/LRR-repeat protein 4

Details

Context

EumetazoaNCBITaxon:6072

mitochondrial outer membraneGO:0005741

mitochondrial depolarization or import failure hypoxia or hypoxia-reoxygenation oxidative, heat or mitochondrial toxin stress in adult tissues developmental clearance (reticulocyte maturation; paternal mitochondria after fertilization)

MitophagyBiological Processmitophagy

Selective macroautophagy of mitochondria in animals. Damaged or unwanted mitochondria are marked by PINK1/Parkin ubiquitin signalling or by outer-membrane receptors (BNIP3/NIX, FUNDC1, and the nematode ALLO-1); ubiquitin-reading or membrane-integral receptors engage Atg8-family proteins on the phagophore; and, in nematodes, FIS-1/FIS-2 complete orderly disposal of fission-derived mitochondrial fragments.

mitophagyGO:0000423

Context

EumetazoaNCBITaxon:6072

mitochondrial outer membraneGO:0005741

Connections

pink1_parkin_marking -> ubiquitin_binding_receptors Provides Input For

Phospho-ubiquitin chains built by PINK1 and Parkin on the outer membrane are the cargo signal that optineurin and NDP52 bind.

pink1_parkin_marking -> bnip3_nix_receptor Positively Regulates

In worms, DCT-1 is ubiquitinated in a PINK-1-dependent manner under oxidative stress and acts genetically with PINK-1 and PDR-1, as recorded in the dct-1 review from the full text of PMID:25896323.

mitophagy_receptor_recognition -> atg8_capture Provides Input For

Receptors present the marked mitochondrion (or paternal organelle) to Atg8-family proteins on the phagophore.

atg8_capture -> fis1_disposal Precedes

In worms, FIS-1/FIS-2 act after LGG-1-positive membranes have engaged fission-derived fragments and before lysosomal fusion. Without them, these intermediates stall as aggregates.

fbxl4_receptor_turnover -> bnip3_nix_receptor Negatively Regulates

SCF-FBXL4 ubiquitinates BNIP3 and NIX for proteasomal degradation, limiting receptor abundance and basal receptor-mediated mitophagy.

Part 1: ubiquitin-dependent marking of damaged mitochondria

PINK1/Parkin ubiquitin signalling on damaged mitochondriaSignaling Pathwaypink1_parkin_marking

PINK1 is a mitochondrially targeted serine/threonine kinase. It is normally imported and degraded, but when import fails on depolarized mitochondria it accumulates on the outer membrane, phosphorylates ubiquitin and the Parkin ubiquitin-like domain at Ser65, and so recruits and activates Parkin. Parkin is an RBR E3 ubiquitin ligase that builds ubiquitin chains on outer-membrane proteins, which PINK1 phosphorylates in turn, making a feed-forward loop. In C. elegans, pink-1 is required for nascent LGG-1-positive mitophagosomes on muscle mitochondria, the Parkin ortholog PDR-1 joins the stalled mitophagy intermediates seen in fis-1 fis-2 mutants, and the receptor DCT-1 is ubiquitinated in a PINK-1-dependent manner under oxidative stress.

type 2 mitophagyGO:0061734

PMID:22354088

Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment.

When import is compromised, PINK1 accumulates on the mitochondrial surface and recruits Parkin from the cytosol.

However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles.

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

Stalled mitophagy intermediates in worm fis-1 fis-2 mutants are the product of PINK-1-induced mitophagy.

do indicate that LGG-1 aggregates in Fis1 mutants are an aberrant product of Pink1-induced mitophagy

PMID:35916724

Selective disruption of Drp1-independent mitophagy and mitolysosome trafficking by an Alzheimer's disease relevant tau modification in a novel Caenorhabditis elegans model.

Oxidative-stress-induced neuronal mitophagy in worms is drp-1-independent and at least partly pink-1-dependent.

Both oxidative-stress-induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1.

Annotons

PINK1 ubiquitin and Parkin kinase

pink1_kinase

Participant: Family: PINK1 mitochondrial serine/threonine kinases

Family:

PINK1 mitochondrial serine/threonine kinasesPANTHER:PTHR22972:SF7

Representative Members: PINK1 (human)UniProtKB:Q9BXM7 PINK-1 (worm)UniProtKB:Q09298

Function

protein serine/threonine kinase activityGO:0004674 Substrates are ubiquitin and the Parkin ubiquitin-like domain (Ser65), shown for human and insect PINK1. They have not been shown biochemically for the worm protein.

Processes

mitophagyGO:0000423

Locations

mitochondrial outer membraneGO:0005741

Damage sensor and initiating kinase. Its stabilization on the outer membrane reports import failure, and its phospho-ubiquitin product recruits and activates Parkin.

PMID:24751536

PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity.

Recombinant PINK1 phosphorylates ubiquitin, and phospho-ubiquitin activates Parkin in cell-free assays.

Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays.

PMID:24660806

Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65.

PINK1 phosphorylates ubiquitin Ser65 directly.

Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro.

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

In worms, pink-1 loss abolishes LGG-1/TOM-70 colocalizing spots (nascent mitophagosomes) on muscle mitochondria.

pink-1 single and pink-1 fis-1 fis-2 triple mutant animals had no colocalizing spots, as expected for a complete block of mitophagy

PMID:26469957

A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans.

In worms, metabolite-induced LGG-1 puncta require pink-1.

Notably, animals with reduced pink-1 no longer have increased mCherry::LGG-1 accumulation in the presence of the metabolite.

Parkin RBR E3 ubiquitin ligase

parkin_ligase

Participant: Family: Parkin RBR E3 ubiquitin ligases

Family:

Parkin RBR E3 ubiquitin ligases No PANTHER family term is given: the UniProt PANTHER cross-reference for human PRKN (PTHR10677) differs from the PAINT family that holds the Parkin node (PTHR11685), which also holds worm PDR-1.

Representative Members: PRKN (human)UniProtKB:O60260 PDR-1 (worm)UniProtKB:Q9XUS3

Function

ubiquitin protein ligase activityGO:0061630 Activated by PINK1 phosphorylation of its ubiquitin-like domain and by binding phospho-ubiquitin. Worm PDR-1 ligase activity has been shown toward CED-10/Rac1; its mitophagy substrates in worms are not identified.

Processes

mitophagyGO:0000423 protein ubiquitinationGO:0016567

Locations

cytosolGO:0005829 mitochondrial outer membraneGO:0005741

E3 ligase that is recruited from the cytosol to damaged mitochondria and coats their outer-membrane proteins with ubiquitin chains, the mark read by ubiquitin-binding receptors.

PMID:19029340

Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.

Parkin is recruited to depolarized mitochondria and mediates their engulfment by autophagosomes.

After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria.

PMID:23754282

Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation.

Parkin catalytic activity depends on PINK1 phosphorylation of Ser65.

Furthermore, formation of the ubiquitin-ester depends on PINK1 phosphorylation of Parkin Ser-65.

PMID:16204351

A Caenorhabditis elegans Parkin mutant with altered solubility couples alpha-synuclein aggregation to proteotoxic stress.

Worm PDR-1 cooperates with ubiquitylation co-enzymes to mediate ubiquitin conjugation.

PDR-1 protein physically associates and cooperates with a conserved degradation machinery to mediate ubiquitin conjugation.

PMID:24625979

PDR-1/hParkin negatively regulates the phagocytosis of apoptotic cell corpses in Caenorhabditis elegans.

The E3-null pdr-1(lg103) allele fails to ubiquitylate CED-10, which shows worm PDR-1 ligase activity in vivo.

As expected, the E3 ligase-null mutant of PDR-1 (lg103) failed to induce CED-10 ubiquitylation

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

Tagged worm PDR-1 is found in the stalled mitophagy intermediates of fis-1 fis-2 mutants.

CFP-tagged Parkin also accumulates in LGG-1 aggregates in the Fis1 mutants

Part 2: receptor recognition of marked mitochondria

Mitophagy receptor recognitionBiological Processmitophagy_receptor_recognition

Receptors bridge the mitochondrion to Atg8-family proteins on the phagophore. Two receptor types exist. Soluble ubiquitin-binding receptors read the Parkin-made ubiquitin mark. Integral outer-membrane receptors carry their own LC3-interacting region and act largely without ubiquitin. The receptors are used in different contexts and lineages and are not interchangeable alternatives for one step; they are grouped as a variant set because each one supplies the mitochondrion-to-phagophore link.

Variant set: Mitophagy receptors by type and lineage by receptor type (ubiquitin-reading soluble receptor or integral outer-membrane receptor) and sequence lineage (One Or More)

Optineurin and NDP52 are the main PINK1/Parkin receptors in human cells and have no clear nematode ortholog. The BNIP3/NIX and FUNDC1 families are conserved between nematodes and mammals. BNIP3 and NIX act in hypoxia-induced and developmental mitophagy, and worm DCT-1 in adult somatic stress-induced mitophagy, genetically with PINK-1/PDR-1. FUNDC1 and FNDC-1 act in hypoxic mitophagy, and FNDC-1 also in the late, ubiquitin-independent phase of paternal mitochondrial elimination. ALLO-1 is nematode-specific and acts in the early, ubiquitin-dependent phase of paternal organelle clearance (allophagy), which also removes the sperm membranous organelles.

Optineurin and NDP52 ubiquitin-binding mitophagy receptors (vertebrate)Biological Processubiquitin_binding_receptors

Optineurin binds polyubiquitin through its UBAN domain and LC3/GABARAP through a LIR motif; NDP52 binds ubiquitin and Atg8-family proteins and its SKICH domain recruits the ULK1 complex. Once on mitochondria, both receptors recruit ULK1, DFCP1 and WIPI1 to start autophagosome formation next to the cargo. TBK1 phosphorylation of optineurin raises its ubiquitin and LC3 binding. These receptors are vertebrate proteins.

Annotons

Optineurin ubiquitin-binding mitophagy receptor

optn_receptor

Participant: Gene Product: OPTN (human)

Gene Product:

OPTN (human)UniProtKB:Q96CV9

Function

protein-macromolecule adaptor activityGO:0030674 The core function in the OPTN review. It bridges polyubiquitin on the cargo to LC3/GABARAP on the phagophore.

Processes

type 2 mitophagyGO:0061734

Locations

cytosolGO:0005829

Reads Parkin-made ubiquitin chains on damaged mitochondria and recruits LC3 and the autophagy initiation machinery.

PMID:25294927

Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation.

Optineurin induces autophagosome formation around damaged mitochondria through its LIR.

Optineurin then induces autophagosome formation around damaged mitochondria via its LC3 interaction region (LIR) domain

PMID:25294927

Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation.

Optineurin associates with ubiquitinated mitochondria through its ubiquitin-binding domain.

allowing optineurin to stably associate with ubiquitinated mitochondria via its ubiquitin binding domain

PMID:21617041

Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.

Optineurin binds LC3/GABARAP through a LIR and ubiquitin through its UBAN domain.

OPTN is an autophagy receptor that binds and localizes with LC3/GABARAP via a phenylalanine-containing LIR motif and ubiquitin via its ubiquitin binding in ABIN and NEMO (UBAN) domains

NDP52 (CALCOCO2) ubiquitin-binding mitophagy receptor

ndp52_receptor

Participant: Gene Product: CALCOCO2/NDP52 (human)

Gene Product:

CALCOCO2/NDP52 (human)UniProtKB:Q13137

Function

autophagy cargo adaptor activityGO:0160247

Processes

mitophagyGO:0000423

Locations

cytoplasmGO:0005737

Main PINK1/Parkin mitophagy receptor together with optineurin. It recruits ULK1, DFCP1 and WIPI1 to mitochondria.

PMID:26266977

The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.

NDP52 and optineurin recruit the autophagy initiation factors to mitochondria.

Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to mitochondria

BNIP3/NIX-family outer-membrane mitophagy receptorBiological Processbnip3_nix_receptor

BNIP3, NIX (BNIP3L) and worm DCT-1 are tail-anchored outer-membrane proteins with an N-terminal LIR. BNIP3 and NIX are HIF targets and act in hypoxic mitophagy; NIX is required for mitochondrial clearance in maturing reticulocytes. DCT-1 is required for stress-induced mitophagy in worms, is ubiquitinated in a PINK-1-dependent manner, and its expression is raised by SKN-1 when mitophagy is impaired.

Annotons

BNIP3/NIX mitochondrion-autophagosome adaptor

bnip3_adaptor

Participant: Family: BNIP3/NIX family

Family:

BNIP3/NIX familyPANTHER:PTHR15186

Representative Members: BNIP3 (human)UniProtKB:Q12983 BNIP3L/NIX (human)UniProtKB:O60238 DCT-1 (worm)UniProtKB:Q09969

Function

mitochondrion autophagosome adaptor activityGO:0140580

Processes

mitophagyGO:0000423

Locations

mitochondrial outer membraneGO:0005741

Membrane-integral receptor that binds LC3/GABARAP (LGG-1 in worms) through its LIR and tethers the mitochondrion to the phagophore.

PMID:20010802

Nix is a selective autophagy receptor for mitochondrial clearance.

NIX is a selective autophagy receptor that binds LC3/GABARAP.

Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins

PMID:20010802

Nix is a selective autophagy receptor for mitochondrial clearance.

Loss of the NIX-LC3/GABARAP interaction slows mitochondrial clearance in reticulocytes.

Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes.

PMID:22505714

Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy.

The BNIP3 LC3-binding site is needed for mitophagy but not for BNIP3 pro-death activity, so the two activities are separable.

Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy.

PMID:25896323

Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

Worm DCT-1 is a key mediator of mitophagy under stress.

We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress

FUNDC1-family ubiquitin-independent mitophagy receptorBiological Processfundc1_receptor

FUNDC1 and worm FNDC-1 are FUN14-family multi-pass outer-membrane proteins. Human FUNDC1 binds LC3 through a Y18xxL21 LIR that is controlled by phosphorylation (ULK1 phosphorylates Ser17) and is required for hypoxia-induced mitophagy. Worm FNDC-1 contributes to hypoxia-reoxygenation mitophagy and to the late removal of paternal mitochondria. Human FUNDC1 also has a separate DRP1-adaptor role at ER-mitochondria contacts that is not modeled here.

Annotons

FUNDC1 mitochondrion-autophagosome adaptor

fundc1_adaptor

Participant: Family: FUNDC1 mitophagy receptors (FUN14 domain)

Family:

FUNDC1 mitophagy receptors (FUN14 domain) No PANTHER family term is given, because the FUN14 family (PTHR21346) also contains FUNDC2 and yeast Fun14, which are not mitophagy receptors.

Representative Members: FUNDC1 (human)UniProtKB:Q8IVP5 FNDC-1 (worm)UniProtKB:Q22252

Function

mitochondrion autophagosome adaptor activityGO:0140580 Shown for human FUNDC1 by LIR mutagenesis. For worm FNDC-1 it is assigned by orthology and genetic requirement; a direct FNDC-1-LGG-1 interaction has not been reported in the cached literature.

Processes

mitophagyGO:0000423

Locations

mitochondrial outer membraneGO:0005741

Ubiquitin-independent receptor for hypoxic mitophagy and, in worms, for the late phase of paternal mitochondrial elimination.

PMID:22267086

Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells.

FUNDC1 binds LC3 through a LIR, and the LIR is needed for hypoxia-induced mitophagy.

FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy.

PMID:24671035

ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy.

ULK1 phosphorylates FUNDC1 at Ser17.

The translocated ULK1 interacts with its substrate FUNDC1 and phosphorylates FUNDC1 at Ser-17.

PMID:31233739

Fndc-1 contributes to paternal mitochondria elimination in C. elegans.

Worm FNDC-1 mediates hypoxic mitophagy and contributes to paternal mitochondria elimination, as a ubiquitin-independent receptor.

This is the first example of a ubiquitin-independent mitophagy receptor playing a role in the selective degradation of sperm mitochondria.

PMID:31153831

Ubiquitination is required for the initial removal of paternal organelles in C. elegans.

Paternal mitochondria that escape the early route are removed later by an fndc-1-dependent process.

they are eventually removed from the embryo in a process that depends on the mitophagy adaptor protein, fndc-1

PMID:33416042

FNDC-1-mediated mitophagy and ATFS-1 coordinate to protect against hypoxia-reoxygenation.

FNDC-1 is the worm FUNDC1 ortholog that responds to hypoxia-reoxygenation.

we provide evidence that FNDC-1 is the C. elegans ortholog of FUNDC1

ALLO-1 allophagy receptor for paternal organelles (nematode)Biological Processallo1_receptor

Nematode-specific. ALLO-1 gathers on ubiquitinated paternal organelles (mitochondria and membranous organelles) soon after fertilization, before the autophagosome forms. It binds LGG-1 through its LIR motif and is needed to recruit the ULK complex around the cargo. Two isoforms with different C-termini prefer different cargo: ALLO-1a mainly membranous organelles, ALLO-1b mainly paternal mitochondria. IKKE-1, the TBK1/IKKepsilon homolog, binds and phosphorylates ALLO-1, and this phosphorylation is needed for ALLO-1 to accumulate on the cargo.

Annotons

ALLO-1 cargo adaptor

allo1_adaptor

Participant: Gene Product: ALLO-1 (worm)

Gene Product:

ALLO-1 (worm)UniProtKB:Q9U389

Function

autophagy cargo adaptor activityGO:0160247 The cargo is paternal organelles, both mitochondria and membranous organelles, so the general cargo-adaptor term is used rather than the mitochondrion-specific adaptor term, as in the allo-1 review.

Processes

mitophagyGO:0000423

Locations

cytoplasmGO:0005737

Ubiquitin-dependent receptor that links paternal organelles to LGG-1 and the ULK complex in the early embryo.

PMID:29255173

The autophagy receptor ALLO-1 and the IKKE-1 kinase control clearance of paternal mitochondria in Caenorhabditis elegans.

ALLO-1 is required for autophagosome formation around paternal organelles and binds LGG-1 through its LIR.

ALLO-1 is essential for autophagosome formation around paternal organelles and directly binds to the worm LC3 homologue LGG-1 through its LC3-interacting region (LIR) motif.

PMID:29255173

The autophagy receptor ALLO-1 and the IKKE-1 kinase control clearance of paternal mitochondria in Caenorhabditis elegans.

ALLO-1 localization depends on ubiquitination of paternal organelles.

this localization depends on the ubiquitin modification of the paternal organelles

PMID:38368448

ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.

ALLO-1 isoforms prefer different cargo, and ALLO-1 is required to recruit the ULK complex around cargo.

In this study, we observed that ALLO-1 has two isoforms with different C-terminal sequences, ALLO-1a and ALLO-1b, which exhibit distinct cargo preference during allophagy.

PMID:38368448

ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.

ALLO-1 is required to recruit the ULK complex around cargo.

indicating that ALLO-1 is required for recruitment of the ULK complex around cargo

Part 3: receptor capture by Atg8-family proteins on the phagophore

Atg8-family docking of mitophagy receptors on the phagophoreBiological Processatg8_capture

Atg8-family proteins (LC3 and GABARAP subfamilies in mammals; LGG-1, the GABARAP-family ortholog, in worms) are conjugated to phosphatidylethanolamine on the phagophore membrane and serve as the binding site for LIR-containing receptors. In worm muscle, nascent mitophagosomes appear as LGG-1 spots on the mitochondrial surface; in the embryo, LGG-1 is recruited to paternal organelles. In human cells the GABARAP subfamily is the main contributor to PINK1/Parkin mitophagy, but Atg8-family proteins are dispensable for engulfment of mitochondria and essential for autophagosome-lysosome fusion, so receptor engagement of Atg8 proteins is not the only way cargo is captured. How the phagophore is built and Atg8 proteins are lipidated belongs to the autophagosome biogenesis module.

Annotons

Phagophore-anchored Atg8-family protein

atg8_family

Participant: Family: Atg8 family (LC3 and GABARAP subfamilies)

Family:

Atg8 family (LC3 and GABARAP subfamilies)PANTHER:PTHR10969

Representative Members: GABARAP (human)UniProtKB:O95166 MAP1LC3B (human)UniProtKB:Q9GZQ8 LGG-1 (worm)UniProtKB:Q09490

Function

phosphatidylethanolamine bindingGO:0008429 The core function in the GABARAP, MAP1LC3B and lgg-1 reviews. Covalent PE anchoring puts the protein on the phagophore. Its receptor-binding (LIR docking) role has no specific GO molecular function term and is described in role_description.

Processes

mitophagyGO:0000423

Locations

autophagosome membraneGO:0000421

Membrane-anchored binding site for the mitophagy receptors. Optineurin, NDP52, NIX, BNIP3 and FUNDC1 bind LC3/GABARAP, and ALLO-1 binds LGG-1 directly through its LIR.

PMID:27864321

Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation.

The GABARAP subfamily is the main Atg8-family contributor to PINK1/Parkin mitophagy in human cells.

identify GABARAP subfamily members as primary contributors to PINK1/Parkin mitophagy and starvation autophagy

PMID:27864321

Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation.

Atg8-family proteins are not needed to engulf mitochondria, but are needed for autophagosome-lysosome fusion.

We show that Atg8s are dispensable for autophagosome formation and selective engulfment of mitochondria, but essential for autophagosome-lysosome fusion.

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

Nascent mitophagosomes in worm muscle are detected as LGG-1 spots on the mitochondrial surface.

Nascent mitophagosomes were detected by colocalization of CFP::LGG-1 (red) and YFP::TOM70 (green) in spots on the surface of mitochondria

PMID:31153831

Ubiquitination is required for the initial removal of paternal organelles in C. elegans.

Blocking organelle ubiquitination prevents LGG-1 recruitment to paternal organelles.

inhibits the recruitment of the autophagy protein, LGG-1 (homolog of LC3/GABARAP), to paternal organelles

Part 4: completion of orderly disposal of fission-derived mitochondrial fragments (nematode)

FIS-1/FIS-2-dependent disposal of damaged mitochondria (nematode)Biological Processfis1_disposal

Established in C. elegans only. After stress-induced, MFF/DRP-1-dependent fission, the FIS1-family outer-membrane proteins FIS-1 and FIS-2 act redundantly at a late step of mitophagy, before fusion with lysosomes. Fis1 joins a DRP-1-containing complex at the ER-mitochondria interface but is not needed for DRP-1 recruitment or for fission. In fis-1 fis-2 mutants, large LGG-1-positive aggregates containing mitochondrial fragments, DRP-1 and PDR-1 build up. Their formation requires mff, drp-1 and pink-1. FIS-1 is also needed to remove UV-C-induced mitochondrial DNA damage. Whether mammalian FIS1 has the same late role is not modeled here, because human FIS1 has no gene review in this repository.

Annotons

FIS-1 outer-membrane disposal adaptor

fis1_adaptor

Participant: Gene Product: FIS-1 (worm)

Gene Product:

FIS-1 (worm)UniProtKB:Q20291

Function

molecular adaptor activityGO:0060090 Family-level adaptor activity (TPR fold) as in the fis-1 review. Its binding partners in this step are not defined.

Processes

mitophagyGO:0000423

Locations

mitochondrial outer membraneGO:0005741

Late-acting outer-membrane factor that keeps disposal of fission-derived fragments orderly. Acts redundantly with FIS-2.

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

Fis1 acts late in removal and is not needed for DRP-1 entry into the MAM or for fission.

Fis1 is part of the MAM complex and contributes to a late stage of the removal process but is not required for entry of Drp1 into the MAM or fission

PMID:24058863

Effects of mutations in mitochondrial dynamics-related genes on the mitochondrial response to ultraviolet C radiation in developing Caenorhabditis elegans.

fis-1 knockdown blocks removal of UV-C-induced mtDNA damage, like drp-1 knockdown.

RNAi knockdown of fis-1 inhibited mtDNA damage removal similarly to drp-1

FIS-2 outer-membrane disposal adaptor

fis2_adaptor

Participant: Gene Product: FIS-2 (worm)

Gene Product:

FIS-2 (worm)UniProtKB:Q6AHP8

Function

molecular adaptor activityGO:0060090

Processes

mitophagyGO:0000423

Locations

mitochondrial outer membraneGO:0005741

FIS1 paralog that acts redundantly with FIS-1 in disposal. It also has a minor, separate pro-apoptotic role downstream of CED-3.

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

Stalled intermediates in fis-1 fis-2 mutants contain LGG-1, DRP-1 and mitochondrial fragments.

causing the formation of large aggregates containing LGG-1, DRP-1, and remnants of mitochondria

PMID:24196833

Mutations in Fis1 disrupt orderly disposal of defective mitochondria.

Mff-dependent fission acts upstream of the Fis1-dependent step.

Inhibition of aggregate formation by a block in Mff-dependent fission shows that Mff acts upstream of the Fis1-dependent step in this process.

Part 5: basal restraint of receptor-mediated mitophagy (vertebrate)

SCF-FBXL4 degrades BNIP3 and NIX to restrain basal mitophagyRegulatory Stepfbxl4_receptor_turnover

Annotons

FBXL4: SCF substrate adaptor for BNIP3/NIX turnover

fbxl4_receptor_degradation

Participant: Family: F-box/LRR-repeat protein 4

Family:

F-box/LRR-repeat protein 4PANTHER:PTHR13318:SF152

Representative Members: FBXL4 (human)UniProtKB:Q9UKA2

Function

ubiquitin-like ligase-substrate adaptor activityGO:1990756

Substrates: BNIP3 and BNIP3L/NIX mitophagy receptors

Processes

negative regulation of mitophagyGO:1901525

Locations

mitochondrial outer membraneGO:0005741

Substrate-recognition subunit of an outer-membrane SCF ubiquitin ligase that constitutively ubiquitinates BNIP3 and NIX (with the PPTC7 adaptor) for proteasomal degradation, keeping basal receptor-mediated mitophagy low. Biallelic FBXL4 loss raises BNIP3/NIX levels and mitophagy, causing mitochondrial DNA depletion syndrome 13; Bnip3 or Nix knockout rescues Fbxl4-null mice. Annoton terms follow the completed human FBXL4 review. PPTC7 has no gene review here and is not modelled.

file:human/FBXL4/FBXL4-ai-review.yaml

Core function GO:1990756 with GO:1901525, mitochondrial outer membrane, in the SCF ubiquitin ligase complex.

PMID:36896912

A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.

SCF-FBXL4 ubiquitinates BNIP3 and NIX for degradation.

SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation.

PMID:37161784

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.

FBXL4 suppresses basal mitophagy by degrading NIX and BNIP3.

mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy