COA8

Summary: COA8 participates in the mitochondrial response to oxidant challenge.

Reason: Human 143B cells show rapid accumulation of mature tagged COA8 after H2O2 or MitoPQ exposure. In patient fibroblasts, complementation preserves complex IV subunits during MitoPQ challenge, whereas deficient cells lose MT-CO1 significantly at the late time point. This supports the original response process without assigning direct ROS detoxification or treating COA8 accumulation alone as the entire mechanism.

Summary: COA8 associates with CLUH in affinity-purification proteomics.

Reason: The exact IntAct record pairs human Q96IL0 bait with CLUH/O75153 prey in an anti-tag coimmunoprecipitation experiment. CLUH is an mRNA-binding protein, not an established enzyme or transmembrane transporter that would justify those partner-class terms. Retain the positive association as contextual binding; this experiment does not establish direct binary affinity, mitochondrial import activity or a COA8 scaffold role. The project Curation instructions retain supported generic binding as non-core when no justified specific replacement is established; this preserves the CLUH evidence without inferring a native mechanism or assigning the distinct COX10 result to CLUH.

Summary: A second BioPlex record supports the COA8–CLUH association.

Reason: The human Q96IL0–O75153 record retains the bait/prey assignment and C-terminal tandem tag. The genuine full variant describes the AP-MS pipeline and quality controls, but network-wide replication statistics are not assigned to this particular pair. The separate COX10–COA8 record and newer focused COX10 study do not change the partner identity of this original CLUH assertion. The project Curation instructions retain supported generic binding as non-core when no justified specific replacement is established; this preserves the CLUH evidence without inferring a native mechanism or assigning the distinct COX10 result to CLUH.

Summary: MitoCoP directly supports mitochondrial residence at the original proteomic scope.

Reason: Original Table S1 identifies Q96IL0/APOPT1 in the high-confidence mitochondrial proteome and its subtractive-proteomics classification. This supports mitochondrion, without measuring an inner-membrane leaflet or distinguishing current products. Retain the original HTP location. Independent topology evidence belongs to the separately preserved PMID:30552096 assertions and the core location.

Summary: The inherited mitochondrial localization is supported without a historical sidedness claim.

Reason: Current human and mouse experimental records and fly GFP/MitoTracker microscopy provide positive mitochondrial grounding. The target in its own donor list is legitimate descendant evidence. Historical PAINT node placement was not reconstructed; neither these donor observations nor independent human topology makes the original IBA assert conserved matrix-side localization. Retain mitochondrion and preserve the distinct source scopes.

Summary: Human M1/M14 construct targeting supports the original mitochondrial location.

Reason: The 2014 GFP constructs beginning at M1 or M14 colocalize with mitochondria, and the M14-derived protein is processed on import. These are positive mitochondrial-targeting experiments, not a direct membrane-leaflet assay. Retain the source-specific IDA assertion; the independent 2018 topology remains represented separately.

Summary: Retain the original inner-membrane location without assigning the later topology assay to this source.

Reason: The 2014 study demonstrates mitochondrial targeting and processing, but its inspected experiments do not resolve the inner-membrane leaflet. The inherited EXP inner-membrane assertion is biologically consistent with independent 2018 membrane-fractionation evidence. Retain it without claiming that PMID:25175347 itself measured matrix-facing topology or that COA8 is an integral transmembrane protein.

Summary: The same study resolves the matrix-facing side of the inner membrane.

Reason: Carbonate extraction indicates peripheral or relatively loose membrane association. Digitonin protection alone was inconclusive; the subsequent hypotonic-shock and super-resolution experiments support the matrix-facing C terminus. The Results support the specific term despite an inconsistent IMS-facing phrase in the Discussion, which is recorded explicitly in the reference assessment. The same primary study supports this refinement. The separate IDA row 13 retains its own source identity; convergence of two source rows does not require deleting either assertion or adding a NEW annotation.

Proposed replacements: matrix side of mitochondrial inner membrane

Summary: The authentic UniProt vocabulary mapping supports the original inner-membrane term.

Reason: SL-0168 maps inner mitochondrial membrane to the original GO term. It does not encode sidedness. Retain this faithful broad mapping; the separately supported human matrix-side annotation and core supply the more precise location without altering the electronic source assertion.

Summary: COA8 contributes to complex IV biogenesis.

Reason: Human patient-cell complementation restores assembled complex IV and activity. Pulse-chase and assembly-intermediate analyses connect COA8 deficiency to reduced subunit stability and stalled assembly. The later COX10 association provides a plausible early mechanism, while the original evidence already supports the process and does not establish that COA8 is a catalytic or structural subunit of mature complex IV.

Summary: Patient-cell genetics and complementation support complex IV assembly.

Reason: Biallelic human variants accompany isolated complex IV deficiency, and re-expression of the M14-derived COA8 construct partially restores complex IV in patient fibroblasts. The paper also reports acute knockdown cultures whose surviving cells did not show the same COX decrease; this context-dependent result does not negate the patient-cell rescue and later independent assembly evidence.

Summary: COA8 promotes stability of nascent complex IV subunits.

Reason: Mitochondrial pulse labeling detects similar initial protein synthesis but accelerated subsequent loss of COX subunits in deficient human fibroblasts. Complementation and oxidant-challenge experiments support a stabilization role during assembly. This is not a direct protein-folding reaction or a claim that COA8 shields every subunit by physical contact; the newer COX10-binding evidence provides a distinct upstream mechanism.

Summary: The apoptosis family mapping overextends context-dependent mouse findings to human COA8.

Reason: GO:0097193 describes intracellular signaling that triggers apoptotic execution. The recovered 2006 paper provides real positive evidence: mouse Apop-1 expression releases cytochrome c and activates caspases, CypD deficiency and cyclosporin A protect, and antisense expression reduces stimulus-induced death. Its 194-residue Apop-1 and alternative C-terminal Apop-2 constructs are not equated to either current human product. In contrast, PMID:25175347 reports negative human muscle TUNEL/ultrastructure and fibroblast staurosporine comparisons, while expressly leaving other tissues unresolved; PMID:30552096 achieved stable human protein expression and observed no cell death or growth arrest in three human cell lines, including HeLa. These target-specific findings make the family-wide human process assertion overextended. This supersedes the prior non-core retention without declaring the mouse experiments false, interpreting the renamed protein as evidence, or asserting that every possible human context lacks an apoptosis role.

Summary: Human biochemical and imaging evidence supports the matrix side of the inner membrane.

Reason: The specific localization follows the Results: membrane association is combined with hypotonic-shock protease protection and super-resolution imaging of tagged full-length COA8. The initial digitonin experiment was inconclusive and the Discussion contains an opposing IMS-facing phrase. The experimental Results and current curated location support this assertion, with sidedness not generalized to the untested current short product.