Affinage

CHCHD2

Coiled-coil-helix-coiled-coil-helix domain-containing protein 2 · UniProt Q9Y6H1

Length
151 aa
Mass
15.5 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHCHD2 (also called MNRR1) is a bi-organellar protein that functions as both a mitochondrial respiratory chain regulator and a stress-responsive nuclear transcription factor, with established roles in cristae maintenance, apoptosis suppression, and neuronal survival. In the mitochondrial intermembrane space, CHCHD2 is imported via Mia40, forms heterodimers with CHCHD10, directly binds and activates cytochrome c oxidase (through Abl2-mediated Tyr-99 phosphorylation inducing conformational changes in COX helices IX/X), suppresses OMA1-mediated cleavage of OPA1 to preserve cristae integrity, interacts with Mic10 to maintain MICOS complex stability, binds Bcl-xL to inhibit Bax-mediated apoptosis, and promotes F1F0-ATPase assembly (PMID:25315652, PMID:27913209, PMID:39094247, PMID:25476776, PMID:32338760, PMID:35830185, PMID:37488867). Under stress, mitochondrial import of CHCHD2 is blocked, enabling its nuclear accumulation where it activates transcription of oxygen-responsive element (ORE)-containing genes by recruiting the RBPJκ/p300 coactivator complex, induces the mitochondrial unfolded protein response upstream of ATF5, and can also sequester SMAD4 to mitochondria to suppress TGFβ signaling (PMID:33257573, PMID:41592630, PMID:27810911). Mutations in CHCHD2 cause autosomal-dominant Parkinson disease; the T61I mutation causes protein precipitation within mitochondria exerting dominant-negative effects on wild-type CHCHD2 solubility, recruits casein kinase 1ε/δ to phosphorylate α-synuclein promoting its aggregation, impairs KGDH-dependent TCA cycle metabolism leading to lipid peroxidation, and reduces striatal dopamine levels (PMID:32068847, PMID:37578019, PMID:40011434, PMID:41237231).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2014 High

    Establishing CHCHD2 as a dual-function protein resolved how a single gene coordinates mitochondrial respiration and hypoxia-responsive transcription: CHCHD2 binds COX in the intermembrane space (imported via Mia40) to support COX activity, and also acts as a transcription factor at a novel oxygen-responsive element in the nucleus.

    Evidence Subcellular fractionation, co-immunoprecipitation with COX, transcription reporter assays, and siRNA knockdown in human cells

    PMID:25315652

    Open questions at the time
    • Mechanism of conditional nuclear versus mitochondrial partitioning not defined
    • No structure of CHCHD2–COX interaction available
    • Oxygen-responsive element binding specificity not mapped at single-nucleotide resolution
  2. 2014 High

    Identifying CHCHD2 as an anti-apoptotic factor revealed a mitochondrial mechanism upstream of MOMP: CHCHD2 binds Bcl-xL and prevents Bax oligomerization, placing it as a gatekeeper of cytochrome c release.

    Evidence Reciprocal co-immunoprecipitation, Bax oligomerization assays, and cytochrome c release/caspase activation after siRNA knockdown

    PMID:25476776

    Open questions at the time
    • Direct binding interface between CHCHD2 and Bcl-xL not structurally resolved
    • Whether this anti-apoptotic role is redundant with CHCHD10 is unknown
  3. 2016 High

    Discovering Abl2-mediated Tyr-99 phosphorylation explained how COX activation by CHCHD2 is regulated and linked a PD-associated Q112H mutation to defective kinase interaction and impaired respiration.

    Evidence In vitro kinase assay, phospho-site mutagenesis, oxygen consumption measurement, patient mutation analysis

    PMID:27913209

    Open questions at the time
    • Whether Tyr-99 phosphorylation is dynamically reversed by a phosphatase is unknown
    • How Abl2 itself is regulated inside mitochondria is not established
  4. 2016 High

    Demonstrating that CHCHD2 sequesters SMAD4 to mitochondria to suppress TGFβ signaling established a non-canonical signaling role for a mitochondrial protein in directing stem cell fate toward neuroectoderm.

    Evidence Co-immunoprecipitation, subcellular fractionation, TGFβ reporter assay, overexpression/knockdown with neuroectodermal differentiation readout in hPSCs

    PMID:27810911

    Open questions at the time
    • Whether this SMAD4 sequestration operates in differentiated neurons is unknown
    • Stoichiometry of CHCHD2–SMAD4 interaction not determined
  5. 2017 High

    Cross-species genetic studies in Drosophila established that CHCHD2 loss causes dopaminergic neuron degeneration and that CHCHD2 partners with MICS1 to regulate cytochrome c's dual role in OXPHOS and apoptosis, linking mitochondrial dysfunction to PD-relevant neurodegeneration.

    Evidence Drosophila CHCHD2 loss-of-function, rescue by human wild-type but not PD-mutant CHCHD2, co-immunoprecipitation with MICS1 and cytochrome c

    PMID:28589937

    Open questions at the time
    • Structural basis for MICS1–CHCHD2 interaction undefined
    • Whether MICS1 interaction is required for anti-apoptotic function versus respiration not separated
  6. 2018 High

    Biochemical demonstration that CHCHD2 and CHCHD10 form a ~220 kDa heterodimer that is essential for respiratory chain complex I assembly and is disrupted by disease mutations resolved their functional interdependence.

    Evidence Reciprocal co-immunoprecipitation, BN-PAGE, oxygen consumption in patient fibroblasts with ALS-linked CHCHD10 R15L, and CHCHD10 scaffolding of CHCHD2 phosphorylation

    PMID:29121267 PMID:29540477 PMID:30084972

    Open questions at the time
    • Stoichiometry of the heterodimer within the ~220 kDa complex is unclear
    • How CHCHD10 scaffolds Abl2 to promote CHCHD2 phosphorylation structurally is unresolved
  7. 2019 High

    Linking CHCHD2 to the MICOS complex via super-resolution co-localization and showing that PD mutations impair MICOS and cristae structure established cristae organization as a core function of CHCHD2.

    Evidence CRISPR isogenic hESC lines, super-resolution microscopy, BN-PAGE of MICOS components, CHCHD2 mutations R145Q and Q126X

    PMID:30496485

    Open questions at the time
    • Whether CHCHD2 binds MICOS directly or via CHCHD10 was not fully resolved at this stage
  8. 2019 High

    Demonstrating that CHCHD2 T61I promotes α-synuclein aggregation through mitochondrial mislocalization in Drosophila, iPSC neurons, and patient brain provided the first mechanistic link between a CHCHD2 PD mutation and synucleinopathy.

    Evidence Drosophila genetics, iPSC-derived dopaminergic neurons, brain autopsy immunofluorescence, sarkosyl-insoluble α-synuclein fractionation

    PMID:31600778

    Open questions at the time
    • Precise mechanism by which mitochondrial dysfunction triggers α-synuclein aggregation not delineated
    • Whether other CHCHD2 mutations also promote synucleinopathy not tested
  9. 2020 High

    Identifying OMA1 as the protease suppressed by CHCHD2/CHCHD10 explained how their loss leads to OPA1 cleavage and cristae disruption, unifying observations from knockout and knock-in mouse models.

    Evidence CHCHD2/CHCHD10 double-knockout mice and CHCHD10 mutant knock-in mice, OMA1 activity and OPA1 cleavage assays

    PMID:32338760

    Open questions at the time
    • Whether CHCHD2 directly inhibits OMA1 catalytic activity or prevents substrate access is unknown
    • Tissue-specific differences in OMA1 regulation not explored
  10. 2020 High

    Revealing that CHCHD2 competes with P32 for YME1L binding to stabilize OPA1 provided an independent cristae-protective mechanism distinct from OMA1 suppression, and showed CHCHD2 integrates multiple pathways of OPA1 regulation.

    Evidence Co-immunoprecipitation of CHCHD2–P32–YME1L trimeric complex in Drosophila, OPA1 level quantification, genetic epistasis with Marf

    PMID:31907391

    Open questions at the time
    • Whether the P32/YME1L mechanism operates in mammalian cells is not directly shown
    • Relative contribution of OMA1 versus YME1L pathway to cristae loss not quantified
  11. 2020 High

    Characterizing T61I CHCHD2 as forming insoluble precipitates within mitochondria that dominantly trap wild-type CHCHD2 explained the dominant-negative inheritance pattern and identified cysteine-dependent IMS import as distinct from the N-terminal targeting sequence.

    Evidence Solubility assays, subcellular fractionation, cysteine mutagenesis, ROS and apoptosis measurements in human cells

    PMID:32068847

    Open questions at the time
    • Structure of the aggregated T61I CHCHD2 species not resolved
    • Whether other twin-CX9C proteins are co-precipitated is unknown
  12. 2020 High

    Demonstrating that nuclear CHCHD2 activates the mitochondrial unfolded protein response upstream of ATF5 and promotes mitochondrial biogenesis resolved how CHCHD2 compensates for mitochondrial dysfunction through transcriptional reprogramming.

    Evidence CHCHD2 overexpression in MELAS cybrids, nuclear/mitochondrial fractionation under stress, ATF5 quantification in CHCHD2-KO cells

    PMID:33257573

    Open questions at the time
    • Direct CHCHD2 binding to ATF5 regulatory elements not shown by ChIP
    • Whether UPRmt activation is protective or pathogenic in chronic disease contexts is unclear
  13. 2022 High

    Showing that CHCHD2/CHCHD10 suppress OMA1 under basal conditions and translocate to cytosol under stress to attenuate eIF2α-mediated integrated stress response added a cytosolic signaling role and positioned the twins as bidirectional stress modulators.

    Evidence Co-immunoprecipitation with OMA1 and eIF2α, CCCP stress paradigm, siRNA knockdown with phospho-eIF2α readout

    PMID:35173147

    Open questions at the time
    • Whether eIF2α interaction is direct or mediated through a kinase complex is unclear
    • In vivo relevance of cytosolic translocation not demonstrated
  14. 2022 Medium

    Identifying Mic10 as a direct CHCHD2 interactor and showing that CHCHD2 protects MICOS integrity against MPP+ toxicity provided direct biochemical evidence for the previously observed MICOS phenotype.

    Evidence Co-immunoprecipitation with Mic10, BN-PAGE and 2D-SDS-PAGE of MICOS, shRNA knockdown and lentiviral overexpression, MPTP mouse model

    PMID:35830185

    Open questions at the time
    • Reciprocal pulldown of Mic10–CHCHD2 not shown
    • Whether CHCHD2 is a stoichiometric MICOS subunit or a regulatory interactor is unclear
  15. 2023 High

    Identifying casein kinase 1ε/δ as recruited by cytosolic T61I-CHCHD2 to phosphorylate α-synuclein and neurofilament established a druggable kinase mechanism linking CHCHD2 mutation to synucleinopathy, validated by kinase inhibitor rescue.

    Evidence Co-immunoprecipitation in Neuro2a cells, Csnk1e/d inhibitor treatment, CHCHD2 T61I knock-in mice, patient iPSC-derived dopaminergic neurons

    PMID:37578019

    Open questions at the time
    • Whether Csnk1e/d recruitment occurs in idiopathic PD without CHCHD2 mutations is unknown
    • How cytosolic CHCHD2 physically recruits Csnk1e/d is not structurally defined
  16. 2024 High

    Resonance Raman spectroscopy revealed that CHCHD2 binding induces structural changes around COX heme sites (helices IX and X), providing the first biophysical mechanism for how CHCHD2 stimulates electron transfer and proton pumping.

    Evidence Visible resonance Raman spectroscopy of purified CcO ± CHCHD2 in reduced and CO-bound states

    PMID:39094247

    Open questions at the time
    • Atomic-resolution structure of the CHCHD2–CcO complex is still lacking
    • Whether CHCHD10 modulates the same structural changes is untested
  17. 2024 Medium

    Demonstrating that CHCHD2 interacts with F1F0-ATPase and promotes its assembly, lost in the T61I mutant, expanded CHCHD2's role beyond Complex IV to include ATP synthase regulation.

    Evidence Mass spectrometry, co-immunoprecipitation, BN-PAGE for ATPase assembly, AAV-mediated expression in MPTP mouse model

    PMID:37488867

    Open questions at the time
    • Direct binding site on F1F0-ATPase not mapped
    • Whether ATPase assembly defect is primary or secondary to cristae disruption is unresolved
  18. 2025 High

    Unbiased metabolomics revealed that CHCHD2 loss specifically reduces KGDH activity in the TCA cycle (not phenocopied by CHCHD10 loss), causing α-ketoglutarate accumulation and lipid peroxidation rescued by lipoic acid, establishing a CHCHD2-specific metabolic vulnerability.

    Evidence Metabolomics of purified mitochondria from CHCHD2-KO mice and human dopaminergic neurons, KGDH activity assay, lipoic acid rescue of lipid peroxidation and phospho-α-synuclein

    PMID:40011434

    Open questions at the time
    • How CHCHD2 regulates KGDH levels or activity mechanistically is unknown
    • Whether lipoic acid rescue translates to neuroprotection in vivo long-term is untested
  19. 2025 High

    Defining RBPJκ/p300 as the nuclear transcription coactivator complex recruited by CHCHD2, and HIF2α as a competitor at the ORE, resolved the molecular mechanism of CHCHD2's transcriptional function and its regulation under pseudohypoxia.

    Evidence Co-immunoprecipitation of CHCHD2–RBPJκ–p300, domain/peptide mutagenesis, ChIP of HIF2α at CHCHD2 promoter, pharmacological rescue with nitazoxanide in MELAS cybrids

    PMID:40710331 PMID:41592630

    Open questions at the time
    • Crystal structure of CHCHD2–RBPJκ complex unavailable
    • Genome-wide map of CHCHD2-dependent ORE targets in neurons is lacking
  20. 2025 High

    Comprehensive phenotyping of T61I knock-in mice demonstrated that CHCHD2 accumulates in Lewy body precursors in idiopathic PD brain and that the mutation causes broad mitochondrial interactome disruption, whole-body metabolic shift to glycolysis, and reduced striatal dopamine, establishing CHCHD2 as central to PD pathogenesis.

    Evidence CRISPR T61I knock-in mice, spatial genomics, proteomics, immuno-EM of human PD brain, metabolic cage analyses; complemented by whole-body CHCHD2-KO lipidomics and dopamine measurements

    PMID:41053020 PMID:41237231

    Open questions at the time
    • Whether CHCHD2 accumulation in Lewy bodies is causative or consequential in idiopathic PD is unresolved
    • Longitudinal neurodegeneration in knock-in mice not yet fully characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive functional characterization, an atomic-resolution structure of CHCHD2 (alone or in complex with COX, CHCHD10, or RBPJκ) has not been determined, and the precise mechanism by which CHCHD2 regulates KGDH and F1F0-ATPase assembly remains unknown.
  • No high-resolution structure of CHCHD2 or its complexes
  • Mechanism of KGDH regulation by CHCHD2 uncharacterized
  • Whether CHCHD2 therapeutic peptides are effective in PD models in vivo is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005739 mitochondrion 8 GO:0005634 nucleus 5 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ABL2BCL2L1C1QBPCHCHD10CYCSMIC10RBPJKSMAD4
Complex memberships
CHCHD2–CHCHD10 heterodimerCytochrome c oxidase (COX)MICOS complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 CHCHD2 (MNRR1) is imported to the mitochondrial intermembrane space via a Mia40-mediated pathway, where it binds directly to cytochrome c oxidase (COX) and this association is required for full COX activity. In the nucleus, CHCHD2 acts as a transcription factor that binds a novel promoter element (oxygen-responsive element, ORE) in COX4I2 and its own promoter, stimulating transcription under hypoxic conditions. Subcellular fractionation, co-immunoprecipitation, COX activity assay, transcription reporter assay, siRNA knockdown with multiple functional readouts (membrane potential, ROS, growth rate) Mitochondrion High 25315652
2016 CHCHD2 binding to COX is promoted by phosphorylation at tyrosine-99, and this phosphorylation is mediated by Abl2 kinase (ARG) inside mitochondria, stimulating respiration. A disease-associated Q112H mutation impairs interaction with Abl2 kinase, leading to defective tyrosine phosphorylation and reduced respiration. In vitro kinase assay, phospho-site mutagenesis, co-immunoprecipitation, oxygen consumption assay, analysis of patient mutation Biochimica et biophysica acta. Molecular cell research High 27913209
2014 CHCHD2 binds to Bcl-xL and inhibits mitochondrial accumulation and oligomerization of Bax, thereby suppressing mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Loss of mitochondrial CHCHD2 prior to MOMP attenuates the ability of Bcl-xL to prevent Bax activation. Co-immunoprecipitation, siRNA knockdown, apoptosis assay (cytochrome c release, caspase activation), Bax oligomerization assay Cell death and differentiation High 25476776
2017 CHCHD2 binds to cytochrome c together with the Bax inhibitor-1 superfamily member MICS1, dynamically regulating cytochrome c function in both oxidative phosphorylation and cell death signaling. Loss of CHCHD2 in Drosophila causes abnormal mitochondrial matrix structures, impaired oxygen respiration, oxidative stress, and dopaminergic neuron loss, rescued by human CHCHD2 but not PD-associated mutants. Co-immunoprecipitation, Drosophila genetic loss-of-function, human CHCHD2 rescue, mitochondrial morphology/respiration assays Nature communications High 28589937
2018 CHCHD2 and CHCHD10 form a stable heterodimer complex (~220 kDa by BN-PAGE), co-localizing in distinct mitochondrial foci. The R15L CHCHD10 ALS mutation destabilizes CHCHD10, abolishes the 220 kDa complex, impairs Complex I assembly, and reduces cellular respiration, while increasing steady-state CHCHD2 levels. Reciprocal co-immunoprecipitation, blue-native PAGE, immunofluorescence co-localization, oxygen consumption assay in patient fibroblasts Human molecular genetics High 29121267
2018 CHCHD2 is preferentially stabilized by loss of mitochondrial membrane potential under stress, and CHCHD10 oligomerization depends on CHCHD2 expression. CHCHD2 and CHCHD10 form heterodimers that increase in abundance in response to mitochondrial stress, demonstrated using knockout cell lines and a heterodimer incorporation assay. CHCHD2/CHCHD10 double knockout cell lines, BN-PAGE, co-immunoprecipitation, mitochondrial uncoupling stress paradigms Human molecular genetics High 30084972
2019 PD-linked CHCHD2 mutations R145Q and Q126X impair interaction with CHCHD10 and reduce MICOS (mitochondrial contact site and cristae organizing system) components, leading to loss of mitochondrial cristae. CHCHD2 physically co-localizes with MICOS by super-resolution microscopy, and knockdown of either CHCHD2 or CHCHD10 reduces MICOS levels and mitochondrial cristae. CRISPR-Cas9 isogenic hESC lines, super-resolution microscopy, co-immunoprecipitation, BN-PAGE, mitochondrial function assays Human molecular genetics High 30496485
2020 Loss of CHCHD2 and CHCHD10 activates the mitochondrial stress peptidase OMA1, which cleaves the long form of OPA1 (L-OPA1), disrupting mitochondrial cristae. OMA1 activation is also observed in mutant CHCHD10 knock-in mice, establishing L-OPA1 cleavage as a shared mechanism for cristae abnormalities from both CHCHD10 mutation and CHCHD2/CHCHD10 loss. C2/C10 double knockout mice, mutant C10 knock-in mice, OMA1 functional assay, OPA1 cleavage assessment, mitochondrial morphology Human molecular genetics High 32338760
2020 CHCHD2 regulates mitochondrial morphology by stabilizing OPA1 protein levels. CHCHD2 competes with the chaperone-like protein P32 for binding to the YME1L protease; when CHCHD2 is present, YME1L-mediated OPA1 degradation is reduced. Loss of Chchd2 in Drosophila reduces Opa1 levels and causes mitochondrial fragmentation, partially rescued by Marf overexpression. Drosophila loss-of-function genetics, co-immunoprecipitation (CHCHD2–P32–YME1L complex), immunoblotting of OPA1 levels, rescue experiments Cell death and differentiation High 31907391
2022 Under physiological conditions, CHCHD2 and CHCHD10 interact with OMA1 and suppress its protease activity, restraining mitochondrial integrated stress response (mtISR) initiation and OPA1 processing for mitochondrial fusion. Under stress (CCCP treatment), CHCHD2 and CHCHD10 translocate to the cytosol and interact with eIF2α, attenuating mtISR overactivation by suppressing eIF2α phosphorylation. Co-immunoprecipitation, siRNA knockdown, CCCP stress treatment, eIF2α phosphorylation assay, OMA1 activity assay Cell death & disease High 35173147
2018 CHCHD10 copurifies with cytochrome c oxidase (COX) and up-regulates COX activity by serving as a scaffolding protein required for CHCHD2 (MNRR1) phosphorylation, mediated by ABL2 kinase. Nuclear CHCHD10 interacts with and augments activity of the transcriptional repressor CXXC5 to down-regulate ORE-containing genes. Co-purification with COX, kinase activity assay, transcription reporter assay, Co-IP with CXXC5 The Journal of biological chemistry High 29540477
2020 CHCHD2 precipitates inside mitochondria when harboring the T61I PD mutation, and mitochondrial targeting of CHCHD2 depends on the four cysteine residues in the C-terminal CHCH domain rather than the N-terminal predicted targeting sequence. T61I CHCHD2 exerts a dominant-negative effect by inducing precipitation of wild-type CHCHD2 and increases mitochondrial ROS and apoptosis preventable by antioxidants. Subcellular fractionation, solubility assay, cysteine mutagenesis, ROS measurement, apoptosis assay in human cells Human molecular genetics High 32068847
2016 CHCHD2 primes neuroectodermal differentiation of human pluripotent stem cells by binding and sequestering SMAD4 to the mitochondria, thereby suppressing TGFβ signaling pathway activity. Co-immunoprecipitation, subcellular fractionation, TGFβ reporter assay, CHCHD2 overexpression/knockdown with neuroectodermal differentiation readout The Journal of cell biology High 27810911
2015 CHCHD2 protein-protein interactions include the hub proteins C1QBP (a mitochondrial protein) and YBX1 (a nuclear oncogenic transcription factor), identified by affinity purification mass spectrometry and validated by in vivo proximity ligation. CHCHD2 knockdown in NSCLC cells attenuates cell proliferation, migration, and mitochondrial respiration. Affinity purification mass spectrometry, proximity ligation assay, siRNA knockdown, cell migration and respiration assays Molecular cancer research : MCR Medium 25784717
2023 The T61I mutant CHCHD2 mislocalizes to the cytosol in Neuro2a cells (rather than mitochondria), where it recruits casein kinase 1ε/δ (Csnk1e/d), which phosphorylates neurofilament and α-synuclein forming cytosolic aggresomes. A Csnk1e/d inhibitor substantially suppresses phosphorylation of these substrates and improves neurodegenerative phenotypes in CHCHD2 T61I mice and patient-derived dopaminergic neurons. Immunofluorescence localization, co-immunoprecipitation, phosphorylation assays, kinase inhibitor treatment, knock-in and transgenic mice, patient iPSC-derived neurons EMBO molecular medicine High 37578019
2019 CHCHD2 T61I mutation promotes α-synuclein aggregation through mitochondrial dysfunction. In Drosophila, CHCHD2 T61I loses mitochondrial localization in the presence of α-synuclein. Mislocalization of CHCHD2 T61I was also observed in patient brain tissue. Drosophila genetics, iPSC-derived dopaminergic neurons, brain autopsy, sarkosyl-insoluble α-synuclein fractionation, immunofluorescence Human molecular genetics High 31600778
2020 CHCHD2 overexpression rescues mitochondrial dysfunction in MELAS cells by acting primarily as a nuclear transcription activator, inducing mitochondrial unfolded protein response (UPRmt), autophagy, and mitochondrial biogenesis. Under stress, CHCHD2 import into mitochondria is blocked, allowing nuclear accumulation to enhance transcription. CHCHD2 knockout cells display ~40% reduction in ATF5 protein, placing CHCHD2 upstream of the UPRmt mediator ATF5. CHCHD2 overexpression in MELAS cybrids, nuclear/mitochondrial fractionation under stress, ATF5 protein quantification in KO cells, UPRmt marker analysis Proceedings of the National Academy of Sciences of the United States of America High 33257573
2025 Loss of CHCHD2 in mouse brains and human dopaminergic neurons decreases the rate-limiting TCA cycle enzyme α-ketoglutarate dehydrogenase (KGDH), leading to elevated α-ketoglutarate and increased lipid peroxidation. Treatment with lipoic acid (a KGDH cofactor/antioxidant) reduces lipid peroxidation and phosphorylated α-synuclein in CHCHD2-deficient neurons. This KGDH pathway effect is specific to CHCHD2 and not observed with CHCHD10 loss. Unbiased metabolomics of purified mitochondria, CHCHD2 KO mice and human dopaminergic neurons, KGDH activity assay, lipoic acid rescue Nature communications High 40011434
2022 CHCHD2 interacts with Mic10 (a core MICOS component) as shown by co-immunoprecipitation. Overexpression of CHCHD2 protects against MPP+-induced MICOS impairment and mitochondrial dysfunction, while CHCHD2 knockdown impairs MICOS stability as assessed by BN-PAGE and 2D-SDS-PAGE. Co-immunoprecipitation, BN-PAGE, 2D-SDS-PAGE, shRNA knockdown, lentiviral overexpression, MPTP mouse model Chinese medical journal Medium 35830185
2024 CHCHD2 binds cytochrome c oxidase (CcO) from the intermembrane space and induces structural changes around the heme peripheries of CcO in the reduced state, particularly affecting helices IX and X (which are near the heme sites and involved in proton uptake). Helix IX is exposed to the IMS and likely the site of CHCHD2 docking; helix X connects both hemes and may facilitate proton pumping. Visible resonance Raman spectroscopy of purified CcO±CHCHD2 in reduced and CO-bound states Journal of inorganic biochemistry High 39094247
2025 CHCHD2 nuclear transcriptional activation is mediated by interaction with RBPJκ and recruitment of the co-activator p300 to the oxygen-responsive element (ORE). A minimal domain of CHCHD2 is sufficient for this nuclear function, and peptides based on this domain can activate transcription by enhancing p300–RBPJκ interaction. Co-immunoprecipitation of CHCHD2–RBPJκ–p300 complex, deletion/peptide mutagenesis, transcription reporter assay, UPRmt and biogenesis pathway activation assays Mitochondrion High 41592630
2024 The C1QBP protein regulates the stability of CHCHD2 and CHCHD10 proteins and is required to maintain the integrity of the C1QBP/CHCHD2/CHCHD10 complex. CHCHD2 deficiency leads to decreased neural cell viability, mitochondrial structural and functional impairment, and upregulation of autophagy under stress; a crucial motif (aa125-133) is responsible for CHCHD2 protein stability. Co-immunoprecipitation, siRNA knockdown of C1QBP and CHCHD2, domain deletion analysis, cell viability and mitophagy assays Molecular neurobiology Medium 38453793
2024 CHCHD2 acts as a repressive transcription factor that inhibits RNase H1 expression to promote R-loop accumulation. SIRT1 interacts with CHCHD2 and deacetylates it, forming a CHCHD2/SIRT1 corepressor complex at the RNase H1 promoter. G9a methyltransferase methylates the RNase H1 promoter and inhibits CHCHD2/SIRT1 recruitment. ChIP assay, co-immunoprecipitation (CHCHD2–SIRT1), siRNA knockdown, transcription reporter, G9a inhibitor treatment Cell insight Medium 37388553
2022 CHCHD2 as a transcription factor directly binds target gene promoters including those in the Notch/osteopontin pathway (identified by ChIP-seq). CHCHD2-overexpressing hepatocytes activate hepatic stellate cells by upregulating osteopontin downstream of Notch signaling, promoting liver fibrosis. YAP/TAZ-TEAD signaling induces CHCHD2 expression via TEAD1 interaction. ChIP-seq, hepatocyte-specific AAV-CHCHD2 overexpression, Chchd2 knockout mice, Notch inhibitor treatment, Co-IP (CHCHD2–TEAD1) JCI insight Medium 36477358
2024 CHCHD2 interacts with F1F0-ATPase (identified by mass spectrometry and confirmed by co-immunoprecipitation), and overexpression of wild-type CHCHD2 promotes F1F0-ATPase assembly, whereas T61I-mutant CHCHD2 has lost this regulatory ability. Mass spectrometry, co-immunoprecipitation, BN-PAGE for ATPase assembly, AAV-mediated in vivo expression in MPTP mouse model Neural regeneration research Medium 37488867
2024 CHCHD2 downregulation in hPSCs attenuates Rho-associated protein kinase (ROCK) activity, conferring resistance to single-cell dissociation-induced death. This pathway places CHCHD2 upstream of ROCK in the regulation of anoikis-related cell death in human embryonic stem cells. Epigenetic repression analysis, CHCHD2 knockdown/reconstitution in hESCs, ROCK activity assay, cell death assay after enzymatic dissociation Cellular and molecular life sciences : CMLS Medium 38214772
2025 HIF2α binds the CHCHD2/MNRR1 promoter and inhibits transcription by competing with RBPJκ. In MELAS cells, pseudohypoxia-stabilized HIF2α (due to reduced PHD3) transcriptionally reduces CHCHD2/MNRR1 levels. Nitazoxanide/tizoxanide restore CHCHD2 transcription by reducing HIF2α through PHD3 induction. ChIP assay (HIF2α at CHCHD2 promoter), promoter competition assay, PHD3 and HIF2α manipulation in MELAS cybrids, drug screening with compound library Cells Medium 40710331
2018 CHCHD2 T61I mutation causes increased interaction with CHCHD10 and results in reduced steady-state CHCHD10 protein levels. Patient fibroblasts with CHCHD2 T61I show mitochondrial ultrastructural alterations similar to those caused by CHCHD10 mutations, suggesting CHCHD10 loss-of-function is involved in T61I PD pathogenesis. Co-immunoprecipitation, immunoblotting in patient fibroblasts, transmission electron microscopy Neurobiology of aging Medium 30530185
2025 In CHCHD2 T61I knock-in mice, CHCHD2 protein accumulates preferentially in the substantia nigra, mitochondrial protein-protein interactions are broadly disrupted, and there is a whole-body metabolic shift toward glycolysis with elevated mitochondrial ROS. CHCHD2 protein accumulates in early Lewy aggregates in idiopathic PD brain, and CHCHD2 gene expression correlates with α-synuclein levels in vulnerable dopaminergic neurons. CRISPR knock-in mice, spatial genomics, proteomics (protein-protein interaction network), immune-electron microscopy, metabolic cage analyses, respiratory exchange ratio measurement Science advances High 41237231
2025 In mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex; its abundance increases in response to mitochondrial dysfunction. Loss of CHCHD2 reduces striatal dopamine levels and disrupts lipid homeostasis in mouse brain without abolishing CHCHD10 oligomerization, but enhances cellular vulnerability to mitochondrial stress. Whole-body Chchd2 knockout mice, BN-PAGE for complex analysis, neurotransmitter measurement, lipidomics, mitochondrial stress assays Cell death & disease High 41053020

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. The Lancet. Neurology 273 25662902
2017 Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c. Nature communications 142 28589937
2014 MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion 137 25315652
2014 CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation. Cell death and differentiation 95 25476776
2015 CHCHD2 gene mutations in familial and sporadic Parkinson's disease. Neurobiology of aging 67 26705026
2019 Mutations in CHCHD2 cause α-synuclein aggregation. Human molecular genetics 64 31600778
2018 Loss of CHCHD10-CHCHD2 complexes required for respiration underlies the pathogenicity of a CHCHD10 mutation in ALS. Human molecular genetics 64 29121267
2020 Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations. Human molecular genetics 63 32338760
2022 CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response. Cell death & disease 61 35173147
2019 PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction. Human molecular genetics 58 30496485
2018 The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction. The Journal of biological chemistry 57 29540477
2015 Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders. Neurology 54 26561290
2018 CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10. Human molecular genetics 53 30084972
2015 CHCHD2 Is Coamplified with EGFR in NSCLC and Regulates Mitochondrial Function and Cell Migration. Molecular cancer research : MCR 48 25784717
2019 Twin CHCH Proteins, CHCHD2, and CHCHD10: Key Molecules of Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia. International journal of molecular sciences 46 30791515
2021 Mitochondrial CHCHD2: Disease-Associated Mutations, Physiological Functions, and Current Animal Models. Frontiers in aging neuroscience 45 33967741
2020 Chchd2 regulates mitochondrial morphology by modulating the levels of Opa1. Cell death and differentiation 41 31907391
2016 The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages. The Journal of cell biology 41 27810911
2018 Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction. Neurology. Genetics 40 30338296
2020 Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms. Proceedings of the National Academy of Sciences of the United States of America 39 33257573
2020 ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons. Neurobiology of disease 30 32437855
2016 Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration. Biochimica et biophysica acta. Molecular cell research 28 27913209
2020 CHCHD2 harboring Parkinson's disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2. Human molecular genetics 25 32068847
2019 Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 24 31526091
2017 MNRR1, a Biorganellar Regulator of Mitochondria. Oxidative medicine and cellular longevity 24 28685009
2024 Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure. Nature communications 23 39174523
2015 CHCHD2 connects mitochondrial metabolism to apoptosis. Molecular & cellular oncology 22 27308501
2016 Mutational scanning of the CHCHD2 gene in Han Chinese patients with Parkinson's disease and meta-analysis of the literature. Parkinsonism & related disorders 21 27269965
2015 Mutation analysis of CHCHD2 gene in Chinese familial Parkinson's disease. Neurobiology of aging 21 26343503
2015 Cyclic adenosine monophosphate response element-binding protein transcriptionally regulates CHCHD2 associated with the molecular pathogenesis of hepatocellular carcinoma. Molecular medicine reports 20 25625293
2023 CHCHD2 and CHCHD10-related neurodegeneration: molecular pathogenesis and the path to precision therapy. Biochemical Society transactions 19 37021679
2022 CHCHD2 p.Thr61Ile knock-in mice exhibit motor defects and neuropathological features of Parkinson's disease. Brain pathology (Zurich, Switzerland) 19 36322611
2018 CHCHD10 is involved in the development of Parkinson's disease caused by CHCHD2 loss-of-function mutation p.T61I. Neurobiology of aging 19 30530185
2022 Increased CHCHD2 expression promotes liver fibrosis in nonalcoholic steatohepatitis via Notch/osteopontin signaling. JCI insight 18 36477358
2015 Lack of CHCHD2 mutations in Parkinson's disease in a Taiwanese population. Neurobiology of aging 18 26725463
2019 Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis. BMC cancer 17 31046734
2024 CHCHD2 up-regulation in Huntington disease mediates a compensatory protective response against oxidative stress. Cell death & disease 16 38341417
2018 Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population. Journal of Alzheimer's disease : JAD 16 29376860
2023 CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia‑induced invasion and therapeutic resistance. International journal of oncology 15 37654190
2015 Mutation analysis of CHCHD2 in Canadian patients with familial Parkinson's disease. Neurobiology of aging 15 26639156
2022 Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2. Human molecular genetics 14 34791217
2015 CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with lissencephaly. Genomics 14 26188257
2022 CCT6A and CHCHD2 Are Coamplified with EGFR and Associated with the Unfavorable Clinical Outcomes of Lung Adenocarcinoma. Disease markers 13 35937942
2023 Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response. Developmental neurobiology 12 36799027
2022 CHCHD2 maintains mitochondrial contact site and cristae organizing system stability and protects against mitochondrial dysfunction in an experimental model of Parkinson's disease. Chinese medical journal 12 35830185
2022 CHCHD2 and CHCHD10: Future therapeutic targets in cognitive disorder and motor neuron disorder. Frontiers in neuroscience 12 36061599
2020 CHCHD2 decreases docetaxel sensitivity in breast cancer via activating MMP2. European review for medical and pharmacological sciences 11 32572940
2025 Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models. Nature communications 10 40011434
2024 Neuroprotective role of CHCHD2 in Parkinson's disease: Insights into the GPX4-related ferroptosis pathway. Free radical biology & medicine 10 39566750
2022 Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway. iScience 10 36339251
2021 Reduced erythrocytic CHCHD2 mRNA is associated with brain pathology of Parkinson's disease. Acta neuropathologica communications 10 33685516
2016 Genetic analysis of CHCHD2 gene in Chinese Parkinson's disease. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 10 27626775
2022 Pathological characterization of a novel mouse model expressing the PD-linked CHCHD2-T61I mutation. Human molecular genetics 9 35786718
2018 Mutation analysis of CHCHD2 and CHCHD10 in Italian patients with mitochondrial myopathy. Neurobiology of aging 9 29519717
2018 Knockdown of CHCHD2 inhibits migration and angiogenesis of human renal cell carcinoma: A potential molecular marker for treatment of RCC. Oncology letters 9 30655828
2016 Mutation analysis of CHCHD2 gene in Chinese Han familial essential tremor patients and familial Parkinson's disease patients. Neurobiology of aging 9 27814991
2016 Analysis of CHCHD2 gene in familial Parkinson's disease from Calabria. Neurobiology of aging 9 27839905
2023 Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2. EMBO molecular medicine 8 37578019
2022 CHCHD2 Regulates Mitochondrial Function and Apoptosis of Ectopic Endometrial Stromal Cells in the Pathogenesis of Endometriosis. Reproductive sciences (Thousand Oaks, Calif.) 7 35157262
2018 Identification of CHCHD2 mutations in patients with Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal dementia in China. Molecular medicine reports 7 29749507
2018 Generation of induced pluripotent stem cell line (ZZUi007-A) from a 52-year-old patient with a novel CHCHD2 gene mutation in Parkinson's disease. Stem cell research 7 30237140
2017 Genetic analysis of CHCHD2 and CHCHD10 in Italian patients with Parkinson's disease. Neurobiology of aging 7 28108040
2016 Genetic analysis of CHCHD2 in a southern Spanish population. Neurobiology of aging 7 27839904
2024 Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes. Acta neuropathologica 6 38750212
2023 MNRR1 is a driver of ovarian cancer progression. Translational oncology 6 36641875
2016 Genetic analysis of the CHCHD2 gene in a cohort of Chinese patients with Parkinson disease. Neuroscience letters 6 27353515
2024 CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease. Neural regeneration research 5 37488867
2023 The CHCHD2/Sirt1 corepressors involve in G9a-mediated regulation of RNase H1 expression to control R-loop. Cell insight 5 37388553
2020 Mitochondria Autoimmunity and MNRR1 in Breast Carcinogenesis: A Review. Journal of cancer immunology 5 33615312
2018 CHCHD2 mutational screening in Brazilian patients with familial Parkinson's disease. Neurobiology of aging 5 30342766
2016 Genetic analysis of the CHCHD2 gene in Chinese patients with familial essential tremor. Neuroscience letters 5 27717833
2024 Epigenetic repression of CHCHD2 enhances survival from single cell dissociation through attenuated Rho A kinase activity. Cellular and molecular life sciences : CMLS 4 38214772
2024 Genetic and pharmacologic p32-inhibition rescue CHCHD2-linked Parkinson's disease phenotypes in vivo and in cell models. Journal of biomedical science 4 38395904
2024 Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction. Molecular neurobiology 4 38453793
2024 Resonance Raman spectral analysis of the heme site structure of cytochrome c oxidase with its positive regulator CHCHD2. Journal of inorganic biochemistry 4 39094247
2023 What is the role of CHCHD2 in adrenal tumourigenesis? Endocrine 4 37221428
2024 CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism. bioRxiv : the preprint server for biology 3 39257750
2022 Downregulation of CHCHD2 may Contribute to Parkinson's Disease by Reducing Expression of NFE2L2 and RQCD1. Current neurovascular research 3 35388756
2018 [Value of CHCHD2 as a potential marker of non-small cell lung cancer: analysis of 60 cases]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 3 29643040
2025 Impaired mitochondrial degradation of CHCHD2 promotes metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma by upregulating VEGFA. Oncogene 2 40025232
2025 CHCHD2 rescues the mitochondrial dysfunction in iPSC-derived neurons from patient with Mohr-Tranebjaerg syndrome. Cell death & disease 2 40075073
2025 LncRNA MALAT1 Facilitates HIV-1 Replication by Upregulation of CHCHD2 and Downregulation of IFN-I Expression. Molecular & cellular proteomics : MCP 2 40414289
2025 CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology. Science advances 2 41237231
2023 Evidence for the participation of CHCHD2/MNRR1, a mitochondrial protein, in spontaneous labor at term and in preterm labor with intra-amniotic infection. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 2 36941246
2023 Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 2 37349086
2022 Production of a human iPSC line from an early-onset Parkinson's disease patient with a novel CHCHD2 gene truncated mutation. Stem cell research 2 35944313
2025 Cortical organoids reveal human-specific roles of METTL5 in neurodevelopment via regulation of CHCHD2. bioRxiv : the preprint server for biology 1 40672170
2025 Pseudohypoxia-Stabilized HIF2α Transcriptionally Inhibits MNRR1, a Druggable Target in MELAS. Cells 1 40710331
2024 A mitochondrial regulator protein, MNRR1, is elevated in the maternal blood of women with preeclampsia. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 1 38220225
2026 Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides. Mitochondrion 0 41592630
2026 CHCHD2, Rather than FBXO7, Plays an Essential Role in Modulating the MPP+-Induced mtUPR. ACS chemical neuroscience 0 41640382
2026 Gamabufotalin impedes NSCLC progression by inhibiting the mitochondrial factor CHCHD2 and modulating XAF1 expression. Biochemical pharmacology 0 41692347
2026 CHCHD2 links mitochondrial dysfunction and α-synuclein misfolding in Parkinson's disease. Trends in neurosciences 0 41763921
2026 CHCHD2: a bi-organellar fulcrum of mitochondrial homeostasis and reproductive pathology. European journal of obstetrics, gynecology, and reproductive biology 0 41996908
2025 Therapeutic Potential of CHCHD2 in Ischemia-Reperfusion Injury: Mechanistic Insights into Nrf2-Dependent Antioxidant Defense in HK2 Cells. International journal of molecular sciences 0 40649864
2025 Effects of pathological mutations on the CHCHD2 monomer structure: A study by AlphaFold3 linked to the generation of conformational ensembles. Computers in biology and medicine 0 40714407
2025 Role of the mitochondrial regulatory factor CHCHD2 in neurodegenerative diseases. Frontiers in neuroscience 0 40963812
2025 The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain. Cell death & disease 0 41053020
2024 Generation of a human iPSC line from a Parkinson's disease patient with a novel CHCHD2 mutation (p.R145Q). Stem cell research 0 38631182
2023 D130A variant on Parkinson 22-related CHCHD2 is predicted to have decreased protein movement. microPublication biology 0 38188421