Affinage

CHCHD6

MICOS complex subunit MIC25 · UniProt Q9BRQ6

Length
235 aa
Mass
26.5 kDa
Annotated
2026-04-28
22 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHCHD6 (Mic25) is a peripheral subunit of the mitochondrial contact site and cristae organizing system (MICOS) at the inner membrane, where it maintains cristae architecture and supports oxidative phosphorylation. It directly binds mitofilin/MIC60 via its C-terminal domain and interacts with SAM50 at the outer membrane; its depletion causes cristae structural defects, reduced oxygen consumption, and diminished ATP production, though it is dispensable for the stability of other core MICOS subunits (PMID:22228767, PMID:25781180, PMID:26530328). CHCHD6 also influences mitochondrial DNA distribution, which regulates calcium-phosphate mineral precursor stabilization in chondrocytes and cartilage calcification (PMID:41864783). In the context of Alzheimer's disease, the APP intracellular domain directly suppresses CHCHD6 transcription, and CHCHD6 loss promotes APP accumulation on mitochondria-associated ER membranes and accelerates amyloidogenic processing; restoring CHCHD6 in an AD mouse model reduces neuropathology and cognitive impairment (PMID:36104602).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2007 Medium

    The identity of CHCHD6 as part of a mitofilin-containing inner membrane complex was unknown; co-immunoprecipitation revealed CHCHD6 alongside SAM50, CHCHD3, metaxins, and DnaJC11, establishing it as a mitochondrial complex component.

    Evidence Monoclonal antibody immunocapture from HeLa mitochondrial extracts

    PMID:17624330

    Open questions at the time
    • Single Co-IP study without reciprocal pull-down from CHCHD6 bait
    • Functional role of CHCHD6 within the complex not addressed
    • Stoichiometry and topology not determined
  2. 2012 High

    Whether CHCHD6 had a direct functional role in cristae maintenance was untested; siRNA knockdown showed severe cristae morphology defects, reduced ATP and oxygen consumption, and domain-mapping demonstrated a direct C-terminal interaction with mitofilin, establishing CHCHD6 as a functional participant in cristae organization.

    Evidence siRNA knockdown in human cells, TEM, co-IP with domain-deletion constructs, metabolic assays

    PMID:22228767

    Open questions at the time
    • Whether CHCHD6 is essential or redundant with paralogous subunits not resolved
    • Mechanism by which CHCHD6 loss disrupts cristae not defined at a structural level
  3. 2015 High

    The hierarchical importance of CHCHD6 within the MICOS complex was unclear; systematic knockdown and knockout studies showed that CHCHD6 depletion does not destabilize other MICOS subunits, positioning it as a peripheral rather than core subunit, though its loss still reduces cristae density.

    Evidence Systematic siRNA knockdown of MICOS subunits and TALEN-mediated CHCHD6 KO with TEM and immunoblot in human cells

    PMID:25781180 PMID:26530328

    Open questions at the time
    • Discrepancy between studies on severity of cristae and metabolic phenotypes upon CHCHD6 loss
    • Specific contribution of CHCHD6 versus CHCHD3 to MICOS assembly not fully separated
  4. 2016 Medium

    Whether pathogenic mutations in the paralog CHCHD10 affected CHCHD6-containing complexes was unknown; patient fibroblast analysis showed CHCHD10 mutations cause MICOS disassembly including CHCHD6 destabilization, linking CHCHD6 to neuromuscular disease-associated MICOS disruption.

    Evidence Co-IP and immunoblot in patient fibroblasts carrying CHCHD10 mutations, TEM

    PMID:26666268

    Open questions at the time
    • CHCHD6 role inferred from complex membership rather than direct manipulation
    • Whether CHCHD6 itself harbors disease-causing variants not tested
  5. 2018 Medium

    A physiological role of CHCHD6 in whole-organ metabolism was unexplored; hepatic knockdown in mice improved steatosis and insulin resistance by shifting metabolism from oxidative phosphorylation toward glycolysis, establishing CHCHD6 as a regulator of liver energy balance.

    Evidence In vivo siRNA in mouse liver, Seahorse metabolic flux assay in vitro

    PMID:29361464

    Open questions at the time
    • Long-term consequences of hepatic CHCHD6 loss not assessed
    • Mechanism linking reduced respiration to improved insulin sensitivity not defined
  6. 2022 High

    Whether CHCHD6 participated in Alzheimer's disease pathogenesis was unknown; a multi-method study showed that the APP intracellular domain binds the CHCHD6 promoter to suppress its transcription, that CHCHD6 and APP mutually stabilize each other, and that CHCHD6 restoration in AD mice rescues neuropathology and cognition, establishing a feedforward loop between APP processing and mitochondrial dysfunction.

    Evidence ChIP, co-IP, promoter-binding assays, AD mouse model rescue with behavioral and neuropathological readouts

    PMID:36104602

    Open questions at the time
    • Whether CHCHD6 levels are reduced in human AD brain tissue not confirmed in this study
    • Relative contribution of CHCHD6's MICOS role versus its APP-stabilizing role to AD pathology not separated
  7. 2023 Medium

    Whether MICOS subunit loss affects cardiac function was untested; Drosophila cardiac-specific knockdown of the CHCHD3/6 ortholog caused contractility defects, sarcomeric protein loss, and mitochondrial dynamics imbalance, extending CHCHD6's role to cardiac energy homeostasis.

    Evidence Cardiac-specific RNAi in Drosophila with contractility imaging, sarcomeric immunofluorescence, ATP assay

    PMID:37404133

    Open questions at the time
    • Drosophila ortholog encompasses both CHCHD3 and CHCHD6; individual contributions not separable
    • Mammalian cardiac phenotype of CHCHD6 loss not examined
  8. 2026 Medium

    A role for CHCHD6 in mtDNA distribution and biomineralization was previously unrecognized; modulation of CHCHD6 in chondrocytes showed it controls the intertwined state of mtDNA that stabilizes amorphous calcium-phosphate mineral precursors, and targeting CHCHD6 impairs osteoarthritis-associated cartilage calcification.

    Evidence CHCHD6 modulation in chondrocyte and OA models, TEM of mineral precursors, in vivo OA progression assay

    PMID:41864783

    Open questions at the time
    • Mechanism linking CHCHD6 to mtDNA distribution state not molecularly defined
    • Whether the calcification role is MICOS-dependent or independent not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise structural basis of CHCHD6 integration into MICOS, its non-redundant functions relative to paralog CHCHD3, and the molecular mechanism by which it influences mtDNA organization remain unresolved.
  • No high-resolution structure of CHCHD6 within the MICOS complex
  • Individual CHCHD6 versus CHCHD3 contributions to cristae morphology not genetically separated in mammalian systems
  • Direct mechanism of CHCHD6 in mitochondrial calcium uptake not isolated from co-depletion experiments

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005739 mitochondrion 7
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-1643685 Disease 1
Partners
APPCHCHD10CHCHD3MIC60SAM50
Complex memberships
MICOS

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 CHCHD6 was identified as a component of a mitochondrial protein complex co-immunoprecipitated with mitofilin (inner membrane), along with metaxins 1 and 2, SAM50, CHCHD3, and DnaJC11, suggesting a role in protein import and mitochondrial structure maintenance. Monoclonal antibody immunocapture / co-immunoprecipitation FEBS letters Medium 17624330
2012 CHCHD6 (CHCM1) localizes predominantly to the mitochondrial inner membrane; its knockdown causes severe defects in cristae morphology (hollow cristae, loss of structural definitions), reductions in ATP production, oxygen consumption, and cell growth. CHCHD6 directly interacts via its C-terminal end with mitofilin, and knockdown of either protein reduces the other's protein levels, indicating coordinate regulation. Knockdown (siRNA), transmission electron microscopy, co-immunoprecipitation, domain-deletion constructs, oxygen consumption and ATP assays The Journal of biological chemistry High 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/Mitofilin, Mic19/CHCHD3, and Sam50. Knockdown cell lines, immunoblot analysis of complex stability, electron microscopy PloS one Medium 25781180
2015 CHCHD6 (Mic25) physically interacts with Sam50 (outer membrane) and with mitofilin, forming a MICOS complex together with CHCHD3. TALEN-generated CHCHD6 knockout cells show reduced cristae density but no reduction in mitochondrial membrane potential or ATP content, unlike mitofilin knockdown cells. Immunoprecipitation, TALEN-mediated gene knockout, transmission electron microscopy, mitochondrial membrane potential assay, ATP assay Scientific reports High 26530328
2016 CHCHD6 resides within the MICOS complex along with mitofilin, CHCHD3, and CHCHD10; CHCHD10 disease mutations cause MICOS complex disassembly and loss of cristae, establishing CHCHD6 as a constituent of the complex affected by CHCHD10 pathogenic variants. Co-immunoprecipitation, immunoblot of MICOS subunit levels in patient fibroblasts, electron microscopy EMBO molecular medicine Medium 26666268
2018 In vivo knockdown of Chchd6 in mice improved hepatic steatosis and insulin resistance; in vitro downregulation of Chchd6 lowered mitochondrial respiration and caused a shift toward glycolytic metabolism, establishing CHCHD6 as a regulator of mitochondrial respiratory function relevant to NAFLD. In vivo siRNA knockdown in mouse liver, in vitro knockdown, Seahorse metabolic flux assay Cell systems Medium 29361464
2022 CHCHD6 mechanistically connects APP processing and mitochondrial dysfunction in Alzheimer's disease: the APP intracellular domain fragment inhibits CHCHD6 transcription by binding its promoter; CHCHD6 and APP bind and stabilize one another; reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing, induces mitochondrial dysfunction and neuronal cholesterol accumulation; compensation for CHCHD6 loss in an AD mouse model reduces AD neuropathology and cognitive impairment. Chromatin immunoprecipitation, co-immunoprecipitation, cellular and animal AD models, promoter-binding assay, CHCHD6 rescue in AD mouse model with behavioral/neuropathological readouts Acta neuropathologica High 36104602
2023 Cardiac-specific knockdown of Drosophila CHCHD3/6 (ortholog of mammalian CHCHD3/CHCHD6) results in compromised heart contractility, diminished sarcomeric actin and myosin levels, reduced cardiac ATP, and mitochondrial fission-fusion defects, placing the MICOS subunit in a pathway required for actomyosin integrity and cardiac energy supply. Drosophila cardiac-specific RNAi knockdown, heart contractility imaging, immunofluorescence for sarcomeric proteins, ATP assay, mitochondrial morphology analysis eLife Medium 37404133
2024 Knockdown of Chchd6 (together with Mic60) in HepG2 cells lowers mitochondrial Ca2+ uptake and retention and induces oxidative stress, linking CHCHD6 to mitochondrial calcium homeostasis and redox regulation. siRNA knockdown in HepG2 cells, mitochondrial calcium uptake/retention assay, oxidative stress measurement bioRxivpreprint Low bio_10.1101_2024.06.20.599846
2026 CHCHD6 modulates mitochondrial DNA distribution (intertwined state) which stabilizes amorphous calcium-phosphate mineral precursors in chondrocyte mitochondria; targeting CHCHD6 inhibits cartilage calcification and impairs osteoarthritis progression. CHCHD6 modulation in chondrocyte/OA models, electron microscopy of mineral precursors, in vivo OA progression assay Science bulletin Medium 41864783

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 179 17624330
2016 CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO molecular medicine 159 26666268
2015 Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. Biochimica et biophysica acta 159 26477565
2015 QIL1 is a novel mitochondrial protein required for MICOS complex stability and cristae morphology. eLife 143 25997101
2018 Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease. Cell systems 119 29361464
2015 Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits. PloS one 116 25781180
2012 CHCM1/CHCHD6, novel mitochondrial protein linked to regulation of mitofilin and mitochondrial cristae morphology. The Journal of biological chemistry 112 22228767
2015 Mitofilin and CHCHD6 physically interact with Sam50 to sustain cristae structure. Scientific reports 107 26530328
2016 Mic13 Is Essential for Formation of Crista Junctions in Mammalian Cells. PloS one 68 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 25 30427857
2021 A retinoic acid receptor β2 agonist attenuates transcriptome and metabolome changes underlying nonalcohol-associated fatty liver disease. The Journal of biological chemistry 23 34688661
2023 Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity. eLife 18 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 5 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