CHCHD4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045041 protein import into mitochondrial intermembrane space	IBA GO_REF:0000033	ACCEPT	Summary: CHCHD4 is the central oxidoreductase of the MIA pathway that drives import of CX3C/CX9C proteins into the IMS. Core BP annotation. Supporting Evidence: file:human/CHCHD4/CHCHD4-deep-research-falcon.md The mitochondrial IMS contains a dedicated protein import route in which import is coupled to oxidative folding, commonly termed the mitochondrial intermembrane space import and assembly pathway or disulfide relay system.
GO:0051604 protein maturation	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: CHCHD4 catalyzes oxidative folding (disulfide bond introduction) of IMS substrates, which is a form of protein maturation. However this is very generic. The more specific disulfide relay system term is more informative. Reason: Too generic; the specific disulfide relay system annotation is more informative.
GO:0005758 mitochondrial intermembrane space	IBA GO_REF:0000033	ACCEPT	Summary: CHCHD4 is a soluble IMS protein. Confirmed experimentally in human cells (PMID:16185709, PMID:23676665). Core CC annotation. Supporting Evidence: file:human/CHCHD4/CHCHD4-deep-research-falcon.md CHCHD4 is localized to the mitochondrial intermembrane space.
GO:0015035 protein-disulfide reductase activity	IBA GO_REF:0000033	MODIFY	Summary: CHCHD4/Mia40 is an oxidoreductase with a CPC active site that catalyzes disulfide bond formation in substrates. The term protein-disulfide reductase describes the reverse reaction. CHCHD4 actually functions as an oxidase (introduces disulfides) not a reductase. However, the active site cycles between oxidized and reduced states. The IBA annotation follows yeast Mia40. Reason: CHCHD4 primarily acts as a disulfide oxidase/isomerase, introducing disulfide bonds into substrates. Disulfide reductase describes the reverse. Proposed replacements: disulfide oxidoreductase activity Supporting Evidence: file:human/CHCHD4/CHCHD4-deep-research-falcon.md CHCHD4 is defined as the IMS-localized oxidoreductase/import receptor that forms a transient intermolecular disulfide with substrates via its CPC motif.
GO:0005739 mitochondrion	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Too general — CHCHD4 specifically localizes to the IMS. Reason: Subsumed by mitochondrial intermembrane space annotation.
GO:0005758 mitochondrial intermembrane space	IEA GO_REF:0000044	ACCEPT	Summary: Correct. Redundant with IBA and experimental evidence for same term.
GO:0015035 protein-disulfide reductase activity	IEA GO_REF:0000002	MODIFY	Summary: Same concern as IBA — CHCHD4 is primarily an oxidase, not a reductase. Proposed replacements: disulfide oxidoreductase activity
GO:0033108 mitochondrial respiratory chain complex assembly	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: CHCHD4 imports IMS assembly factors (e.g., NDUFB10, COA7) required for respiratory chain complexes. This is a downstream consequence of its import function, not its primary activity. Reason: Secondary effect of CHCHD4 import function, not its direct activity.
GO:0045041 protein import into mitochondrial intermembrane space	IEA GO_REF:0000002	ACCEPT	Summary: Correct. Redundant with IBA for same term.
GO:0005515 protein binding	IPI PMID:26387864 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU...	REMOVE	Summary: Petrungaro et al. 2015 showed Mia40-dependent release of MICU1-MICU2 dimer from MCU. Protein binding is uninformative per guidelines. Reason: Protein binding is uninformative. The MICU1/MICU2 interaction reflects CHCHD4 substrate oxidative folding function.
GO:0005739 mitochondrion	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: Too general — IMS localization is well-established and more specific. Reason: Subsumed by mitochondrial intermembrane space annotation.
GO:0160203 mitochondrial disulfide relay system	IMP PMID:16185709 Functional and mutational characterization of human MIA40 ac...	ACCEPT	Summary: Hofmann et al. 2005 showed that human MIA40 depletion specifically reduced levels of small IMS proteins (DDP1, TIM10A), demonstrating its role in the disulfide relay system. Core BP annotation.
GO:0015035 protein-disulfide reductase activity	IMP PMID:23676665 Protein import and oxidative folding in the mitochondrial in...	MODIFY	Summary: Fischer et al. 2013 confirmed oxidative folding activity in intact mammalian cells. Same concern about reductase vs oxidase terminology. Proposed replacements: disulfide oxidoreductase activity
GO:0160203 mitochondrial disulfide relay system	IMP PMID:21059946 Molecular chaperone function of Mia40 triggers consecutive i...	ACCEPT	Summary: Stojanovski et al. 2010 showed Mia40 triggers consecutive induced folding steps during import. Core BP annotation.
GO:0160203 mitochondrial disulfide relay system	IMP PMID:23676665 Protein import and oxidative folding in the mitochondrial in...	ACCEPT	Summary: Fischer et al. 2013 confirmed the disulfide relay operates in intact mammalian cells. Core BP annotation.
GO:0160203 mitochondrial disulfide relay system	IMP PMID:37159021 A two-step mitochondrial import pathway couples the disulfid...	ACCEPT	Summary: Habich et al. 2023 described a two-step import pathway coupling the disulfide relay with matrix complex I biogenesis. Core BP annotation.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: HTP proteome confirms mitochondrial localization. Too general. Reason: Subsumed by mitochondrial intermembrane space annotation.
GO:0005758 mitochondrial intermembrane space	IMP PMID:37159021 A two-step mitochondrial import pathway couples the disulfid...	ACCEPT	Summary: Habich et al. 2023 confirmed IMS localization in two-step import study.
GO:0015035 protein-disulfide reductase activity	IMP PMID:37159021 A two-step mitochondrial import pathway couples the disulfid...	MODIFY	Summary: Same concern about reductase vs oxidase terminology. Proposed replacements: disulfide oxidoreductase activity
GO:0005758 mitochondrial intermembrane space	EXP PMID:23676665 Protein import and oxidative folding in the mitochondrial in...	ACCEPT	Summary: Fischer et al. 2013 directly demonstrated CHCHD4 in the IMS of intact mammalian cells. Core CC.
GO:0005515 protein binding	IPI PMID:28040730 Mutations in the accessory subunit NDUFB10 result in isolate...	REMOVE	Summary: Friederich et al. 2017 showed NDUFB10 mutations affect CHCHD4-dependent import. Protein binding is uninformative. Reason: Protein binding uninformative. NDUFB10 is a CHCHD4 substrate.
GO:0005515 protein binding	IPI PMID:26004228 Interaction between AIF and CHCHD4 Regulates Respiratory Cha...	REMOVE	Summary: Hangen et al. 2015 showed AIF-CHCHD4 interaction regulates respiratory chain biogenesis. Protein binding is uninformative. Reason: Protein binding uninformative. AIF interaction is better captured by respiratory chain complex assembly annotation.
GO:0005758 mitochondrial intermembrane space	IDA PMID:26004228 Interaction between AIF and CHCHD4 Regulates Respiratory Cha...	ACCEPT	Summary: Hangen et al. confirmed IMS localization by immunofluorescence.
GO:0033108 mitochondrial respiratory chain complex assembly	IMP PMID:26004228 Interaction between AIF and CHCHD4 Regulates Respiratory Cha...	KEEP AS NON CORE	Summary: Hangen et al. 2015 showed AIF-CHCHD4 interaction required for respiratory chain biogenesis. This is a downstream consequence of CHCHD4 import function. Reason: Downstream of CHCHD4 core import/oxidative folding function.
GO:0005515 protein binding	IPI PMID:30885959 Inhibition of proteasome rescues a pathogenic variant of res...	REMOVE	Summary: Mohanraj et al. 2019 showed COA7 is a CHCHD4 substrate rescued by proteasome inhibition. Protein binding is uninformative. Reason: Protein binding uninformative. COA7 is a CHCHD4 import substrate.
GO:0005515 protein binding	IPI PMID:23676665 Protein import and oxidative folding in the mitochondrial in...	REMOVE	Summary: Fischer et al. 2013 studied CHCHD4 substrate interactions in intact cells. Protein binding is uninformative. Reason: Protein binding uninformative. Reflects transient enzyme-substrate disulfide intermediates.
GO:0005739 mitochondrion	IDA PMID:23676665 Protein import and oxidative folding in the mitochondrial in...	MARK AS OVER ANNOTATED	Summary: Too general — IMS is more specific and well-supported. Reason: Subsumed by mitochondrial intermembrane space annotation.
GO:0015035 protein-disulfide reductase activity	IDA PMID:26387864 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU...	MODIFY	Summary: Petrungaro et al. 2015 showed CHCHD4 oxidoreductase activity on MICU1-MICU2 substrates. Same terminology concern. Proposed replacements: disulfide oxidoreductase activity
GO:0005739 mitochondrion	IDA PMID:24101517 Mitochondrial disulfide relay mediates translocation of p53 ...	MARK AS OVER ANNOTATED	Summary: Zhuang et al. 2013 showed CHCHD4 mediates p53 translocation to mitochondria. Too general CC term. Reason: Subsumed by mitochondrial intermembrane space annotation.
GO:0005758 mitochondrial intermembrane space	IDA PMID:16185709 Functional and mutational characterization of human MIA40 ac...	ACCEPT	Summary: Hofmann et al. 2005 directly showed human MIA40 forms soluble complexes in the IMS. Foundational evidence for IMS localization.
GO:0015035 protein-disulfide reductase activity	IMP PMID:19182799 MIA40 is an oxidoreductase that catalyzes oxidative protein ...	MODIFY	Summary: Banci et al. 2009 determined MIA40 solution structure and demonstrated it is an oxidoreductase with a CPC active site. Landmark paper establishing the enzymatic mechanism. Same terminology concern about reductase vs oxidase. Proposed replacements: disulfide oxidoreductase activity

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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