Affinage

CHCHD6

MICOS complex subunit MIC25 · UniProt Q9BRQ6

Length
235 aa
Mass
26.5 kDa
Annotated
2026-06-09
22 papers in source corpus 13 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHCHD6 (MIC25) is a coiled-coil-helix-coiled-coil-helix domain protein of the mitochondrial inner membrane that functions as a peripheral subunit of the MICOS complex governing cristae architecture and mitochondrial bioenergetics (PMID:22228767, PMID:25781180). It was first identified in an inner-membrane assembly captured through mitofilin, containing SAM50, metaxins 1/2, CHCHD3, and DnaJC11 (PMID:17624330), and it directly binds mitofilin/MIC60 via its C-terminal CHCH domain as well as CHCHD3/MIC19 and the outer-membrane component Sam50, bridging inner and outer membranes; CHCHD6 and mitofilin reciprocally stabilize one another at the protein level (PMID:22228767, PMID:26530328). Within MICOS, CHCHD6 belongs to a stable MIC60–MIC19–MIC25 sub-module that persists when MIC13/QIL1 is lost but is not by itself sufficient to form crista junctions (PMID:25997101, PMID:27479602). Loss-of-function studies link CHCHD6 to cristae morphology, ATP production, oxygen consumption, mitochondrial calcium handling and redox homeostasis, and to chemosensitivity in cancer cells [PMID:22228767, PMID:bio_10.1101_2024.06.20.599846]. CHCHD6 stability is set by ubiquitin-dependent degradation through its interaction with the ubiquitin-conjugating enzyme UBC, and disrupting this interaction preserves MICOS integrity and mitochondrial function (PMID:40435285). In Alzheimer's disease models, CHCHD6 and APP mutually bind and stabilize each other while the APP intracellular domain (AICD) represses CHCHD6 transcription, and restoring CHCHD6 reduces neuropathology and cognitive impairment (PMID:36104602).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Medium

    Established that CHCHD6 is a physical constituent of a defined mitochondrial inner-membrane assembly, placing an uncharacterized protein into a specific molecular context.

    Evidence Anti-mitofilin immunocapture and protein identification of the inner-membrane complex

    PMID:17624330

    Open questions at the time
    • Did not define which subunits CHCHD6 directly contacts
    • No functional consequence of complex membership tested
  2. 2012 High

    Defined CHCHD6 as functionally required for cristae integrity and bioenergetics and mapped its direct binding to mitofilin, answering whether the protein is a passive passenger or a structural/regulatory subunit.

    Evidence siRNA knockdown with TEM, ATP and oxygen-consumption assays, Co-IP with CHCH domain mapping and reciprocal knockdown in human cells

    PMID:22228767

    Open questions at the time
    • Mechanism coupling cristae loss to ATP/O2 decline not resolved
    • Interaction with DISC1 not functionally characterized
  3. 2015 High

    Reclassified CHCHD6 as a peripheral rather than core MICOS subunit and showed it bridges the inner membrane (mitofilin) to the outer membrane (Sam50), clarifying its position in the complex architecture.

    Evidence Co-IP, TALEN knockout, TEM, membrane potential and ATP assays, and complexome/proteomics after QIL1 depletion

    PMID:25781180 PMID:25997101 PMID:26530328

    Open questions at the time
    • Discrepancy between knockdown (severe cristae defects) and knockout (milder phenotype) unexplained
    • Stoichiometry and assembly order within MICOS not defined
  4. 2016 Medium

    Showed CHCHD6 resides in a stable MIC60–MIC19–MIC25 sub-module that is necessary but not sufficient for crista junction formation, refining the assembly hierarchy of MICOS.

    Evidence MIC13/QIL1 knockout, complexome profiling, TEM, and patient fibroblast analysis in CHCHD10-mutant disease

    PMID:26666268 PMID:27479602

    Open questions at the time
    • What additional factors complete crista junction formation not identified
    • Direct contribution of CHCHD6 within the sub-module untested
  5. 2018 Medium

    Determined that CHCHD6 is N-myristoylated but, unlike MIC19, does not require this modification for mitochondrial targeting, distinguishing the regulatory logic of paralogous MICOS subunits.

    Evidence In vitro/in vivo metabolic labeling, G2A mutagenesis, fractionation and immunofluorescence

    PMID:30427857

    Open questions at the time
    • Functional purpose of CHCHD6 myristoylation unknown
    • Whether modification affects interactions or stability untested
  6. 2022 Medium

    Linked CHCHD6 to APP biology in Alzheimer's disease via mutual protein stabilization and AICD-mediated transcriptional repression, connecting a mitochondrial structural protein to neurodegenerative pathology.

    Evidence Co-IP, promoter-binding assay, cellular and mouse AD models with behavioral rescue

    PMID:36104602

    Open questions at the time
    • Molecular basis of CHCHD6-APP binding not mapped
    • Single lab; AICD-promoter mechanism not independently confirmed
  7. 2022 Medium

    Identified CHCHD6 as part of a CARD19 interactome in macrophages, hinting at MICOS connections to immune signaling proteins.

    Evidence Co-IP, mass spectrometry and CARD domain-deletion analysis

    PMID:35406738

    Open questions at the time
    • Functional consequence of CARD19-CHCHD6 interaction unknown
    • Directness of CHCHD6 contact not established
  8. 2023 Medium

    Demonstrated an in vivo physiological requirement for the CHCHD3/CHCHD6 ortholog in cardiac contractility and mitochondrial integrity, extending the cristae-maintenance role to tissue function.

    Evidence Drosophila cardiac-specific RNAi with contractility imaging, sarcomeric protein staining, ATP and mitochondrial morphology analysis

    PMID:37404133

    Open questions at the time
    • Drosophila ortholog represents both CHCHD3 and CHCHD6, limiting attribution to CHCHD6
    • Mechanism linking cristae defects to sarcomere loss not resolved
  9. 2025 Medium

    Uncovered ubiquitin-dependent control of CHCHD6 stability through UBC, defining a post-translational mechanism that sets MICOS integrity and mitochondrial function.

    Evidence Proteomics, Co-IP, KD/OE, and Epimedin C disruption with mitochondrial and exercise-performance assays in mice

    PMID:40435285

    Open questions at the time
    • E3 ligase directing CHCHD6 ubiquitination not identified
    • Physiological signals triggering degradation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHCHD6 mechanistically couples cristae architecture to calcium handling, redox balance, and disease-relevant phenotypes, and what defines its specific non-redundant role versus other MICOS subunits, remains unresolved.
  • No structural model of CHCHD6 within MICOS
  • Calcium/redox role rests on combined Mic60+Chchd6 knockdown in a preprint
  • E3 ligase and physiological degradation triggers unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3
Partners
APPCARD19CHCHD3DISC1IMMTSAMM50UBC
Complex memberships
MIC60-MIC19-MIC25 sub-moduleMICOS

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 CHCHD6 was identified as a component of a mitochondrial inner membrane complex containing mitofilin, SAM50, metaxins 1 and 2, CHCHD3, and DnaJC11, immunocaptured via anti-mitofilin monoclonal antibody. Immunoprecipitation with anti-mitofilin monoclonal antibody followed by protein identification FEBS letters Medium 17624330
2012 CHCHD6 (CHCM1) localizes predominantly to the mitochondrial inner membrane; its knockdown causes severe defects in mitochondrial cristae morphology (hollow cristae with loss of structural definition and reduction in electron-dense matrix), reduces cell growth, ATP production, and oxygen consumption. Knockdown by siRNA, transmission electron microscopy, ATP assay, oxygen consumption measurement, immunofluorescence/fractionation for localization The Journal of biological chemistry High 22228767
2012 CHCHD6 directly interacts with mitofilin through its C-terminal coiled-coil-helix-coiled-coil-helix domain, and also interacts with CHCHD3 and DISC1; knockdown of CHCHD6 reduces mitofilin protein levels, and mitofilin knockdown reciprocally reduces CHCHD6 levels, indicating coordinate regulation. Co-immunoprecipitation, domain-mapping experiments, reciprocal knockdown/immunoblot The Journal of biological chemistry High 22228767
2012 CHCHD6 knockdown in human cancer cells enhances chemosensitivity to genotoxic anticancer drugs, while its overexpression increases resistance, linking CHCHD6 to drug response via mitochondrial integrity. siRNA knockdown and overexpression in cancer cell lines, drug sensitivity assays The Journal of biological chemistry Medium 22228767
2015 CHCHD6 (Mic25) is a peripheral subunit of the human MICOS complex; its depletion does not affect cristae morphology or stability of other MICOS components, in contrast to core subunits Mic60, Mic19, and Sam50. siRNA knockdown cell lines, transmission electron microscopy, immunoblotting of MICOS components PloS one Medium 25781180
2015 CHCHD6 physically interacts directly with Sam50 (outer membrane) and mitofilin (inner membrane); TALEN-generated CHCHD6 knockout cells show lower cristae density but maintained mitochondrial membrane potential and ATP content (in contrast to mitofilin knockdown), and knockout of CHCHD6 does not destabilize other MICOS binding partners. Co-immunoprecipitation, TALEN-based knockout, transmission electron microscopy, mitochondrial membrane potential assay, ATP measurement, immunoblotting Scientific reports High 26530328
2015 Loss of QIL1/MIC13 results in accumulation of a MIC60-MIC19-MIC25 (CHCHD6) sub-complex with degradation of MIC10, MIC26, and MIC27, establishing that CHCHD6/MIC25 is part of a stable MIC60-MIC19-MIC25 sub-module within MICOS. Quantitative proteomics after QIL1 depletion, Co-immunoprecipitation eLife Medium 25997101
2016 CHCHD10 resides with mitofilin, CHCHD3, and CHCHD6 within the MICOS complex; CHCHD10 mutations lead to MICOS complex disassembly and loss of cristae, demonstrating CHCHD6 is part of the functional MICOS assembly. Co-immunoprecipitation, patient fibroblast analysis, electron microscopy EMBO molecular medicine Medium 26666268
2016 MIC13 knockout cells retain the MIC60/MIC19/MIC25 (CHCHD6) subcomplex, but this subcomplex alone is not sufficient for crista junction formation, establishing that CHCHD6-containing subcomplex is necessary but not sufficient for CJ integrity. CRISPR/Cas9 knockout, complexome profiling, transmission electron microscopy PloS one Medium 27479602
2018 CHCHD6 (MIC25) undergoes N-myristoylation in vitro and in vivo; however, unlike MIC19, non-myristoylated G2A mutant of MIC25 is not impaired in mitochondrial targeting or membrane binding, indicating N-myristoylation of MIC25 is not required for its mitochondrial localization. In vitro and in vivo metabolic labeling, immunofluorescence, subcellular fractionation, G2A mutagenesis, co-immunoprecipitation PloS one Medium 30427857
2022 CARD19 interacts with MICOS components MIC19, MIC25 (CHCHD6), and MIC60 as identified by mass spectrometry of immunoprecipitates from macrophages, and this interaction is partly dependent on a properly folded CARD domain. Co-immunoprecipitation, mass spectrometry, domain deletion analysis Cells Medium 35406738
2022 CHCHD6 and APP bind and stabilize one another; the APP intracellular domain (AICD) fragment inhibits CHCHD6 transcription by binding its promoter; reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing; compensation for CHCHD6 loss in an AD mouse model reduces neuropathology and cognitive impairment. Co-immunoprecipitation, promoter binding assay, cellular and animal AD models, mouse behavioral testing, immunofluorescence Acta neuropathologica Medium 36104602
2023 Cardiac-specific knockdown of the Drosophila ortholog of CHCHD3/CHCHD6 (dCHCHD3/6) results in drastically compromised heart contractility, diminished sarcomeric actin and myosin levels, reduced cardiac ATP, and mitochondrial fission-fusion defects, consistent with a role in maintaining cristae morphology and ETC assembly. Drosophila cardiac-specific RNAi knockdown, heart contractility imaging, immunofluorescence for sarcomeric proteins, ATP measurement, mitochondrial morphology analysis eLife Medium 37404133
2025 MIC25 (CHCHD6) stability is regulated via ubiquitin-dependent degradation through interaction with ubiquitin-conjugating enzyme UBC; Epimedin C disrupts the MIC25-UBC interaction, preventing MIC25 degradation and maintaining MICOS integrity, ATP production, and mitochondrial cristae structure in skeletal muscle. Proteomic analysis, co-immunoprecipitation, MIC25 overexpression and knockdown, functional assays for mitochondrial function and exercise performance in mice PloS one Medium 40435285
2024 Knockdown of Chchd6 (along with Mic60) in HepG2 cells lowers mitochondrial Ca2+ uptake and retention and induces oxidative stress, demonstrating a role for CHCHD6 in mitochondrial calcium handling and redox homeostasis. siRNA knockdown in HepG2 cells, mitochondrial Ca2+ assays, oxidative stress measurements bioRxivpreprint Low bio_10.1101_2024.06.20.599846

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The mitochondrial inner membrane protein mitofilin exists as a complex with SAM50, metaxins 1 and 2, coiled-coil-helix coiled-coil-helix domain-containing protein 3 and 6 and DnaJC11. FEBS letters 180 17624330
2015 Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. Biochimica et biophysica acta 164 26477565
2016 CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO molecular medicine 160 26666268
2015 QIL1 is a novel mitochondrial protein required for MICOS complex stability and cristae morphology. eLife 148 25997101
2018 Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease. Cell systems 121 29361464
2015 Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits. PloS one 119 25781180
2012 CHCM1/CHCHD6, novel mitochondrial protein linked to regulation of mitofilin and mitochondrial cristae morphology. The Journal of biological chemistry 114 22228767
2015 Mitofilin and CHCHD6 physically interact with Sam50 to sustain cristae structure. Scientific reports 108 26530328
2016 Mic13 Is Essential for Formation of Crista Junctions in Mammalian Cells. PloS one 69 27479602
2019 Comprehensive Proteomic Analysis Reveals Intermediate Stage of Non-Lesional Psoriatic Skin and Points out the Importance of Proteins Outside this Trend. Scientific reports 26 31388062
2018 Identification and characterization of protein N-myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. PloS one 26 30427857
2021 A retinoic acid receptor β2 agonist attenuates transcriptome and metabolome changes underlying nonalcohol-associated fatty liver disease. The Journal of biological chemistry 25 34688661
2023 Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity. eLife 19 37404133
2004 Genotoxicity of goniothalamin in CHO cell line. Mutation research 18 15279832
2022 A CHCHD6-APP axis connects amyloid and mitochondrial pathology in Alzheimer's disease. Acta neuropathologica 11 36104602
2020 Identification of Key Pro-Survival Proteins in Isolated Colonic Goblet Cells of Winnie, a Murine Model of Spontaneous Colitis. Inflammatory bowel diseases 9 31504521
2022 CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology. Cells 8 35406738
2010 FISH mapping in cattle (Bos taurus L.) is not yet out of fashion. Journal of applied genetics 8 21063067
2023 Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence. International journal of molecular sciences 6 36982708
2026 Mitochondria serve as a source of mineral precursors initiating early cartilage calcification in osteoarthritis. Science bulletin 0 41864783
2025 Epimedin C enhances mitochondrial energy supply by regulating the interaction between MIC25 and UBC in rodent model. PloS one 0 40435285
2025 PI3K/AKT/GSK3β regulatory axis in bone mesenchymal stem cells initiates diabetic myocardial infarction via miR-142-3p. World journal of experimental medicine 0 41523760

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