CHCHD10 is a small CHCH-domain protein concentrated in the mitochondrial intermembrane space near cristae. It associates with CHCHD2 in human cells, forming heterodimers and higher-molecular-weight complexes. Human control fibroblasts contain CHCHD10-containing complexes of approximately 170 and 220 kDa; differentiated mouse tissues contain complexes of approximately 100–140 kDa and retain CHCHD10 oligomerization after CHCHD2 loss. The two proteins have partly redundant roles in mitochondrial membrane organization and respiratory homeostasis, including control of OMA1-dependent OPA1 processing. CHCHD10 also promotes cytochrome-c oxidase activity in cellular and purified-component experiments, while a secondary nuclear pool participates in CXXC5-dependent repression of COX4I2 expression in human cells. Pathogenic variants differ in aggregation, residual activity and mitochondrial-stress effects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003674 molecular_function | ND GO_REF:0000015 | REMOVE | Summary: The no-data molecular-function assertion is superseded by established molecular activities. Reason: The original GO:0003674/ND assertion records absence of information about molecular function. Human HEK293, HeLa and primary-fibroblast experiments establish CHCHD2–CHCHD10 heterodimerization with DSG/DSS crosslinking, reciprocal detection, gene-knockout controls and co-IP (PMID:30084972); the independently established nuclear corepressor activity supplies further positive molecular evidence. The no-information assertion is therefore superseded. REMOVE applies to that ND assertion, not to an obsolete GO identifier or to a biological absence of function. Original term, evidence and reference remain archival fields. Specific heterodimerization is retained in the three source-preserving binding refinements and the directly supported core; no redundant NEW assertion is added. |
| GO:0005515 protein binding | IPI PMID:26666268 CHCHD10 mutations promote loss of mitochondrial cristae junc... | KEEP AS NON CORE | Summary: The reported CHCHD10–mitofilin association is supported, despite uncertainty about MICOS membership. Reason: Full PMID:26666268 Results/Fig. 2 report endogenous anti-mitofilin co-IP in human control and S59L fibroblasts, reverse CHCHD10 co-IP in HeLa, and proximity ligation. These establish a positive association under the tested conditions; they do not require a purified binary interface. Later detergent-dependent gradients and controlled co-IP fail to confirm a stable association in some conditions, leaving transient association possible. Retain the original Q16891 partner and generic binding as non-core under the campaign instruction. Do not infer a specific adaptor/scaffold activity or equate this pair result with undisputed MICOS membership. Supporting Evidence: PMID:26666268 mitofilin was immunoprecipitated file:human/CHCHD10/CHCHD10-source-evidence.json |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MODIFY | Summary: CHCHD2 binding can be refined to the independently demonstrated heterodimerization activity. Reason: The original mitochondrial affinity-enrichment screen used tagged ORFs in human cell lines. Eight exact positive IntAct association records match Q8WYQ3/Q9Y6H1 and this PMID. They are not eight purified binding experiments and do not themselves resolve stoichiometry. Independent human crosslinking with CHCHD2/CHCHD10 knockout controls establishes heterodimer formation (PMID:30084972), supporting this specific binding refinement while preserving the original IPI source. The selected normal cache is partial despite its full-text flag; genuine external full Methods were read. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:30496485 PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex ... | MODIFY | Summary: Native human CHCHD2–CHCHD10 association is consistent with heterodimerization. Reason: The actual full paper tests CHCHD10 although its title foregrounds CHCHD2. Endogenous reciprocal co-IP in human SK-N-SH cells, healthy human brain lysate and H9 cells supports the pair. A C-terminal CHCHD2 tag impaired association, and mutant effects were assessed using the stated expression contexts. The specific heterodimer term is supported additionally by PMID:30084972, not inferred merely from co-IP or partner identity. The current IntAct target retrieval lacks an exact record for this PMID; this is a retrieval gap, not negative evidence against the directly inspected experiment. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:30496485 endogenous CHCHD2 pulled down endogenous CHCHD10 file:human/CHCHD10/CHCHD10-source-evidence.json |
| GO:0005515 protein binding | IPI PMID:30530185 CHCHD10 is involved in the development of Parkinson's diseas... | MODIFY | Summary: The variant-context CHCHD2 association belongs to an independently established heterodimerizing pair. Reason: Full Results/Fig. 2B report increased association with CHCHD2 T61I in human SH-SY5Y overexpression experiments. The exact positive curated record carries a CHCHD2 position-61 mutation feature and FLAG tag; it is not separate confirmation of untagged wild-type binding. Independent endogenous human assays in PMID:30084972 establish the CHCHD2–CHCHD10 heterodimer and justify the more informative MF. Preserve the original IPI and Q9Y6H1 source without treating mutant enhancement as the universal native interaction or transferring a Parkinson-disease mechanism to normal CHCHD10. Proposed replacements: protein heterodimerization activity |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: A secondary nuclear activity is supported in human cells. Reason: This PAINT assertion is not rejected because the protein is predominantly mitochondrial. PMID:29540477 detects endogenous nuclear CHCHD10 with fractionation and knockdown-controlled imaging, and shows CXXC5-dependent recruitment to a COX4I2 oxygen-responsive promoter element plus reporter repression. These functional experiments support is_active_in rather than localization alone. The promoter association is protein-dependent and does not establish intrinsic DNA binding. The exact historical PTN000338319 placement was not reconstructed; the listed CHCHD2 donor and positive human CHCHD10 evidence are distinguished from that phylogenetic provenance. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000338319 UNRESOLVED The actual historical PAINT ancestral placement and alignment were not reconstructed. Independent target experiments support the retained activity/process; this does not assert that current donor records reconstruct the historical node. Donor count and target self-reference are not failure criteria. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Human mitochondrial proteomics agrees with the established core compartment. Reason: The full source describes mitochondrial fractionation and quantitative proteomics in human cell lines and explicitly discusses CHCHD10/MIC14 in its mitochondrial-protein analysis. The individual target-peptide table was not independently extracted, so no peptide count or purity claim is supplied. Independent endogenous imaging and protease-protection experiments in PMID:24934289 directly establish mitochondrial localization. The proteomics discussion of possible MICOS linkage does not establish membership in that complex. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: CHCHD10 performs its principal association and organization roles in mitochondria. Reason: The is_active_in qualifier is supported by human mitochondrial CHCHD2 heterodimerization and WT rescue of altered OPA1 processing in CHCHD2/CHCHD10-deficient cells, not by localization alone. Preserve the complete PAINT WITH set, including the target itself: target experimental evidence is legitimate phylogenetic support, not circularity. The historical ancestral-node placement was not reconstructed, and no inference about its validity is made from donor count. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000338319 UNRESOLVED The actual historical PAINT ancestral placement and alignment were not reconstructed. Independent target experiments support the retained activity/process; this does not assert that current donor records reconstruct the historical node. Donor count and target self-reference are not failure criteria. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence places CHCHD10 in its core mitochondrial compartment. Reason: The authentic HPA record has mitochondria as its main subcellular location. Independent endogenous HeLa imaging, mitochondrial fractionation and protease protection support the same location. Preserve the GO_REF:0000052 IDA assertion; no antibody-specific isoform or nuclear exclusion is inferred. |
| GO:0005739 mitochondrion | IDA PMID:20888800 Functional annotation of heart enriched mitochondrial genes ... | ACCEPT | Summary: The early experimental mitochondrial location is independently corroborated. Reason: Only the authentic original abstract was accessible for PMID:20888800; it reports gene-knockdown and respiratory experiments but does not expose the location assay in detail. The original IDA is retained rather than second-guessed from incomplete text. Human endogenous imaging and mitochondrial/mitoplast protease protection in PMID:24934289 independently establish this correct core compartment. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic mitochondrial assignment is biologically correct. Reason: The preserved ARBA, mouse Q7TNL9 and Ensembl identifiers are the original combined mapping. Q7TNL9 is mouse Chchd10; the exact historical combined-rule execution was not reconstructed. Direct human CHCHD10 localization establishes the result independently, so no failure is inferred from the automated provenance or incomplete rule history. |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:24934289 A mitochondrial origin for frontotemporal dementia and amyot... | ACCEPT | Summary: Direct subfractionation supports the mitochondrial intermembrane space. Reason: Full PMID:24934289 Methods/Results distinguish intact mitochondria from digitonin-derived mitoplasts: CHCHD10 is protected in intact organelles but accessible after outer-membrane permeabilization, with SMAC, matrix HSPD1 and membrane controls. Alkali extraction and endogenous immunogold microscopy add topology and cristae-proximity information. These experiments support the original IMS location without requiring an integral transmembrane topology or MICOS membership. Supporting Evidence: PMID:24934289 CHCHD10 is an intermembrane space protein |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: The controlled-vocabulary mapping captures the directly established IMS location. Reason: SL-0169 maps the UniProt mitochondrial intermembrane-space location to the supplied GO term. Independent human protease-protection/mitoplast and microscopy experiments support that compartment. Preserve this electronic source separately from the experimental annotation; proximity to cristae does not by itself identify a named complex. Supporting Evidence: |
| GO:0007005 mitochondrion organization | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial organization is a supported conserved role. Reason: Human mutant and endogenous-loss studies, together with CHCHD10 re-expression in CHCHD2/CHCHD10-deficient human cells, support mitochondrial organization. The existing broad process encompasses the membrane/cristae phenotypes without specifying a direct membrane-remodeling enzyme. Preserve the PAINT node and complete donor set; neither target self-reference nor the number of listed sources is a defect. The exact ancestral reconstruction remains uninspected. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000338319 UNRESOLVED The actual historical PAINT ancestral placement and alignment were not reconstructed. Independent target experiments support the retained activity/process; this does not assert that current donor records reconstruct the historical node. Donor count and target self-reference are not failure criteria. |
| GO:0007005 mitochondrion organization | IEA GO_REF:0000002 | ACCEPT | Summary: The family-based organization mapping agrees with target evidence. Reason: The supplied IPR055304 family mapping is retained. Its organization inference is independently supported by human CHCHD10 localization, variant effects and WT re-expression experiments. These studies justify the existing process, while leaving the immediate molecular route from CHCHD10 association to membrane homeostasis unresolved; no intrinsic protease, chaperone or lipid-transfer activity is inferred from the family name. |
| GO:0007005 mitochondrion organization | IMP PMID:20888800 Functional annotation of heart enriched mitochondrial genes ... | ACCEPT | Summary: The original organization claim is retained with explicit access limits and independent evidence. Reason: The authentic PMID:20888800 abstract reports CHCHD10 knockdown and complex-IV functional effects, but the original full morphology experiment was not recovered. This does not justify rejecting its IMP annotation. Later human cristae/membrane experiments and WT CHCHD10 rescue independently support the existing broad organization role. The 2010 source is not presented as a newly inspected ultrastructure assay. |
| GO:0007006 mitochondrial membrane organization | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-to-human membrane-organization inference is consistent with human experiments. Reason: The exact current Q7TNL9 donor is mouse Chchd10 and carries IMP membrane organization from PMID:28585542. That paper distinguishes endogenous mouse HT22 depletion from human Flag-CHCHD10 WT/R15L/S59L expression in mouse NIH3T3 hosts; it is not all endogenous human evidence. The historical Ensembl transfer was not reconstructed. Human S59L and combined-loss/WT-rescue studies independently establish the retained membrane role, without equating every disease allele with simple loss of function. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q7TNL9 SUPPORTS TRANSFER Official mouse Chchd10 identity and current IMP source PMID:28585542 were inspected, with species/construct limits explicit. Independent human evidence supports the result; exact historical transfer execution remains unresolved. Supporting Evidence: file:human/CHCHD10/CHCHD10-source-evidence.json |
| GO:0007006 mitochondrial membrane organization | ISS GO_REF:0000024 | ACCEPT | Summary: The manually transferred membrane role has correctly identified ortholog support. Reason: Preserve the ISS and mouse Q7TNL9 source. Its current experimental donor annotation cites PMID:28585542, whose endogenous depletion, human-transgene and mouse-host experiments are distinguished in the source ledger. Human CHCHD10 evidence corroborates membrane organization. This is a review of the sound biological result, not a claim to have reconstructed the original curator transfer or to have demonstrated direct CHCHD10 membrane catalysis. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q7TNL9 SUPPORTS TRANSFER Official mouse Chchd10 identity and current IMP source PMID:28585542 were inspected, with species/construct limits explicit. Independent human evidence supports the result; exact historical transfer execution remains unresolved. Supporting Evidence: file:human/CHCHD10/CHCHD10-source-evidence.json |
| GO:0007007 inner mitochondrial membrane organization | IMP PMID:24934289 A mitochondrial origin for frontotemporal dementia and amyot... | ACCEPT | Summary: Human S59L experiments support involvement in inner-membrane organization. Reason: Full patient-fibroblast ultrastructure and matched full-length human WT-versus-S59L expression in HeLa show cristae loss, disorganization or dilation in the mutant contexts. The same paper directly localizes CHCHD10 near cristae in the IMS. These are actual target experiments, but a dominant mutant phenotype alone does not identify normal CHCHD10 as a physical membrane scaffold or fusion enzyme. Independent WT-function studies support retaining the existing involvement term. |
| GO:0007007 inner mitochondrial membrane organization | IMP PMID:26666268 CHCHD10 mutations promote loss of mitochondrial cristae junc... | ACCEPT | Summary: The original cristae phenotype supports the process even though its MICOS model is disputed. Reason: PMID:26666268 tests human S59L patient cells and tagged mutant expression, documenting cristae/complex changes. Its proposed MICOS membership is separately contested and does not erase the actual morphology observations. Independent CHCHD2/CHCHD10 loss and CHCHD10 rescue in human cells support a partly redundant organization role. Avoid treating the tested P34S overexpression phenotype as a universal clinical pathogenicity determination or asserting that CHCHD10 itself cleaves OPA1. |
| GO:0007007 inner mitochondrial membrane organization | IMP PMID:30092269 Loss of MICOS complex integrity and mitochondrial damage, bu... | ACCEPT | Summary: The gene-level inner-membrane role is retained without reversing the original G66V result. Reason: Full PMID:30092269 reports preserved cristae ultrastructure and MICOS assembly in G66V patient fibroblasts, contrasting them with S59L, while documenting network fragmentation. It must not be cited as a positive G66V cristae-disorganization assay. The existing gene-level role is independently supported by human S59L studies and CHCHD10 WT rescue of altered OPA1 processing after combined loss. Preserve the original IMP source and this allele-specific contrast rather than rejecting the role or silently converting a negative ultrastructure result into a positive one. |
| GO:0061617 MICOS complex | IDA PMID:26666268 CHCHD10 mutations promote loss of mitochondrial cristae junc... | UNDECIDED | Summary: Assignment to MICOS remains unresolved because actual complex experiments conflict. Reason: The original source genuinely reports mouse-brain and human-fibroblast BN-PAGE/2D co-migration, native co-IP with mitofilin and proximity ligation. Later human detergent-dependent gradients, controlled reciprocal co-IP and native-complex analysis predominantly separate CHCHD10/CHCHD2 from MICOS; 2025 mouse-tissue complexomics supplies a further distinct-complex result. These are conflicting assignments, not merely lack of access or absence of an essential knockout phenotype. GO:0061617 does not require purified stoichiometric binding or that every component be essential, so a possible transient/peripheral association is not categorically excluded. Preserve the original positive IDA and omit MICOS from the definitive core complex until this context is resolved. Supporting Evidence: PMID:29121267 Neither CHCHD10, nor CHCHD2 co-migrated file:human/CHCHD10/CHCHD10-source-evidence.json |
| GO:0003714 transcription corepressor activity | IDA PMID:29540477 The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Par... | NEW | Summary: CHCHD10 performs a contextual nuclear corepressor activity in human cells. Reason: Full human HEK293 experiments combine CHCHD10-dependent repression of an intact but not mutated COX4I2 oxygen-responsive promoter element, derepression after CHCHD10 knockdown, reciprocal CXXC5 association and CXXC5-dependent recruitment to the endogenous ORE. Together these support repression through a DNA-bound transcription-regulatory complex, which fits GO:0003714. The experiment includes C-terminally tagged expression and knockdown contexts; no direct sequence-specific DNA binding, histone-modifying activity or universal tissue role is inferred. This adds a measured molecular activity, not a new process inferred from mitochondrial stress. Supporting Evidence: PMID:29540477 this inhibition requires an intact ORE file:human/CHCHD10/CHCHD10-source-evidence.json |
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Download this section (compressed HTML)Q: Under which cell, tissue and detergent conditions does CHCHD10 associate with MICOS, and is that association transient or a discrete complex population?
Q: How do human-cell heterodimers relate to the 170/220 kDa complexes in control human fibroblasts and the 100–140 kDa complexes in differentiated mouse tissues, and which changes reflect cell state, detergent conditions or composition?
Q: How general is the CXXC5-dependent nuclear repression pathway beyond the tested human cell lines, and how is it coordinated with mitochondrial CHCHD10 abundance?
Q: Does CHCHD10 contact a catalytic COX subunit directly during stimulation, or act through associated CHCHD2/MNRR1? Positive purified-COX supplementation and human-cell dependence are established. PMID:30084972 explicitly discusses an indirect CHCHD10–COX interaction dependent on CHCHD2. Together with associated components in the COX preparation and unresolved recombinant reagent identity, this leaves the direct-interaction requirement of GO:0008047 unsettled.
Experiment: Compare endogenous complex composition using quantitative native separation and orthogonal crosslinking across human cell types, with knockout controls, matched detergents and absolute subunit stoichiometry.
Experiment: Reconstitute CHCHD10 effects using sequence-defined human protein, COX preparations with quantified associated factors, and OMA1/OPA1 components to distinguish direct regulation from cellular compensation.
Experiment: Test nuclear CXXC5-dependent promoter occupancy and repression with endogenous localization-selective CHCHD10 perturbations and expression-matched rescue.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The immediate molecular route connecting CHCHD10-containing complexes to OMA1/OPA1 and membrane homeostasis remains unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human CHCHD2 heterodimerization, localization, and WT re-expression effects on OPA1 processing are established. SLP2/PHB associations and COX stimulation provide additional functional evidence, but do not by themselves demonstrate a direct protease inhibitor, folding chaperone or ternary scaffold mechanism.
Significance: Separating the normal performed activity from variant aggregation and stress responses is necessary to interpret differing pathogenic mechanisms.
What would resolve it: Use sequence-defined purified components and endogenous expression-matched separation-of-function mutants to distinguish direct protease modulation, proteostasis effects and respiratory-complex regulation.
Provenance (the field's own admissions):
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