Bnip3l (NIX) — mouse (Q9Z2F7) curation notes

Identity and structure

• Mouse Bnip3l / Nix, 218 aa, NIP3 family (PANTHER PTHR15186, subfamily PTHR15186:SF3;
  InterPro IPR010548; Pfam PF06553). UniProt features: C-terminal helical TM 187-207,
  BH3 motif 125-147, N-terminal disordered region 1-66 (file:mouse/Bnip3l/Bnip3l-uniprot.txt).
• Tail-anchored outer mitochondrial membrane protein; cytosolic N-terminus carries the LIR
  (W35 in mouse Q9Z2F7 numbering, residues 31-40 LNSSWVELPM; W36 in human BNIP3L) and the minimal essential region (MER).
• First described as a pro-apoptotic homolog of Nip3/BNIP3 PMID:9867803, localized with
  mitochondrial HSP60 PMID:9867803. Note: nuclear signal arises only when the TM is deleted.
• Self-association / dimer PMID:9867803; TM-mediated homodimer is
  required for robust LC3 recruitment and mitophagy PMID:32286918.

Core function: mitophagy receptor (mouse genetics)

• Two independent mouse knockouts establish NIX as required for programmed mitochondrial
  clearance in reticulocytes:
• PMID:18048346; independent of apoptotic machinery PMID:18048346; not an autophagy inducer
  PMID:18048346; arrest point PMID:18048346.
• PMID:18454133; PMID:18454133; loss of membrane potential is Nix-dependent PMID:18454133.
• LIR-mediated receptor mechanism: PMID:20010802; in vivo PMID:20010802; LIR effect is partial PMID:20010802.
• MER (second motif) in mouse reticulocytes: PMID:22906961; PMID:22906961. The MER binds WIPI2 PMID:37621214.
• Kanki commentary summarising: PMID:20200478

GO mapping: MF GO:0140580 mitochondrion autophagosome adaptor activity (def: "brings together a
mitochondrial membrane and an autophagosome membrane during mitophagy"); BP GO:0000423 mitophagy;
CC GO:0005741 mitochondrial outer membrane. None of GO:0140580 / GO:0000423 is in mouse GOA.

Other programmed / developmental mitophagy (mouse)

• Retinal ganglion cell differentiation and M1 macrophage polarization PMID:28465321; hypoxic induction PMID:28465321

Cell death roles (context-dependent, non-core)

• Overexpression kills cells PMID:9867803.
• Erythroblast apoptosis PMID:17420462
  — Diwan et al. interpret Nix as pro-apoptotic in erythropoiesis, contrasting with the mitophagy
  interpretation from Schweers/Sandoval (Sandoval interpret the RBC loss as secondary to retained
  mitochondria).
• Cardiac/ER death pathways PMID:20418503; ER-Nix dissipates potential via MPTP
  PMID:20418503
• POSH/JNK PMID:17095503 (overexpression, HEK293/PC12).
• Human orthologue B5 inhibits Nip3-induced apoptosis and localizes to NE/ER/mitochondria
  PMID:10381623.
• Hypoxia: BNIP3/BNIP3L promote survival autophagy PMID:19273585.

MALM (MIEAP) — human only

• PMID:21264228 Human cancer
  cell work; transferred to mouse by ISO/ISS/IEA only. Non-core.

Annotations judged problematic

• GO:0051607 defense response to virus (ISO/ISS/IEA from human IDA PMID:9973195): source paper
  only shows binding to viral anti-apoptotic E1B-19K — not host defense. REMOVE.
• GO:0016607 nuclear speck (from HPA antibody staining in human) and GO:0005634 nucleus (IBA):
  nuclear signal only for TM-deleted Nix PMID:9867803. Over-annotation.
• GO:1903747 is obsolete per QuickGO ("this term represents a phenotype and was added in error.
  Consider annotating to regulation of the specific process being regulated (e.g. regulation of
  mitophagy)"); verified 2026-10-10 via QuickGO API (OLS still showed it live).
• GO:0005515 protein binding rows: LC3/GABARAP partners -> MODIFY to GO:0140580; SH3RF1/POSH and
  ATG13 -> REMOVE (uninformative).

PAINT / IBA observations (PTHR15186)

• From the PANTHER tree (treeinfo API, filtered to human/mouse/zebrafish/worm/fly), PTN002689506
  is the vertebrate BNIP3L (NIX) clade node, and PTN002689498 is the vertebrate BNIP3 clade node;
  PTN000795991 is the family root.
• The mitophagy IBD (GO:0000423) sits at PTN001032684 (seeds BNIP3, fly BNIP3, worm dct-1), but
  projects/PANTHER_IBA_REVIEW/family_function_losses.tsv lists an IRD for GO:0000423 at
  PTN002689506 — i.e. the NIX clade is pruned from mitophagy. This is contrary to the strongest
  mitophagy genetics in the family (mouse Nix knockouts). As a consequence mouse Bnip3l has no
  mitophagy IBA.
• PTN002689498 (BNIP3 clade) carries GO:0140580, GO:0005789, GO:0061709 seeded only by human BNIP3,
  so NIX gets no adaptor-activity IBA either. GO:0140580 should be placed at the BNIP3/BNIP3L
  duplication ancestor (or at PTN001032684), and the GO:0000423 IRD on PTN002689506 removed.
• GO:0043653 mitochondrial fragmentation involved in apoptotic process (PTN001032684) is seeded by
  BNIP3 only; no NIX evidence for apoptotic fragmentation.

Deep research

• falcon deep research was launched by the parent agent; not available at time of writing.

Addendum: falcon deep research (arrived after the review was written)

Bnip3l-deep-research-falcon.md (falcon, retried with a longer timeout after a first 600 s timeout)
landed after the annotation review was finished. It was cross-checked against the review and agrees
with its calls: the primary role is a LIR-bearing, tail-anchored mitochondrial autophagy receptor at
the outer mitochondrial membrane, and cell-death outputs are context-dependent and separable from
receptor function. It is cited on the core GO:0140580 annotation. No annotation decision changes.