{"gene":"CHCHD10","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2014,"finding":"CHCHD10 is a mitochondrial protein localized to the intermembrane space and enriched at cristae junctions; overexpression of the S59L mutant allele causes fragmentation of the mitochondrial network and ultrastructural abnormalities including loss, disorganization, and dilatation of cristae in HeLa cells.","method":"Immunofluorescence, subcellular fractionation, electron microscopy, overexpression of mutant allele in HeLa cells","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence, replicated across labs","pmids":["24934289"],"is_preprint":false},{"year":2016,"finding":"CHCHD10 resides within the MICOS (mitochondrial contact site and cristae organizing system) complex together with mitofilin, CHCHD3, and CHCHD6; disease-associated CHCHD10 mutations lead to MICOS complex disassembly, loss of cristae, decreased nucleoid number, impaired mtDNA repair after oxidative stress, and inhibition of apoptosis by preventing cytochrome c release.","method":"Co-immunoprecipitation, patient fibroblast analysis, electron microscopy, nucleoid staining, cytochrome c release assay","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP identifying complex membership, multiple orthogonal functional assays, replicated in patient cells","pmids":["26666268"],"is_preprint":false},{"year":2010,"finding":"CHCHD10 knockdown reduces Complex IV (cytochrome c oxidase) activity in vitro, establishing a role for CHCHD10 in oxidative phosphorylation.","method":"siRNA knockdown, complex IV activity assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro activity assay, single lab","pmids":["20888800"],"is_preprint":false},{"year":2018,"finding":"CHCHD10 associates with membranes in the mitochondrial intermembrane space and directly interacts with its paralog CHCHD2 and with p32/C1QBP; CHCHD10 has a short half-life suggesting a regulatory role; knockdown leads to intramitochondrial iron accumulation; S59L and R15L mutants (but not WT) impair mitochondrial energy metabolism.","method":"Immunoprecipitation/MS interactome, subcellular fractionation, pulse-chase half-life assays, iron measurement, Seahorse bioenergetics, knockout mice","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple orthogonal methods in single rigorous study","pmids":["29112723"],"is_preprint":false},{"year":2018,"finding":"The p.R15L CHCHD10 variant destabilizes the protein and causes defective assembly of mitochondrial Complex I, impaired cellular respiration, and mitochondrial hyperfusion; CHCHD10 and CHCHD2 form a high molecular weight complex (~220 kDa) by blue native PAGE that is absent in patient cells.","method":"Blue native PAGE, immunoprecipitation, oxygen consumption measurement, patient fibroblasts, galactose growth assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — BN-PAGE complex identification plus functional respiration assay in patient cells","pmids":["29121267"],"is_preprint":false},{"year":2018,"finding":"Mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the N-terminal targeting signal and depends on Mia40, which introduces disulfide bonds; the Q108P disease mutation nearly completely blocks mitochondrial import, resulting in cytoplasmic mislocalization; Mia40 overexpression rescues import of CHCHD10 Q108P.","method":"Truncation mutagenesis, Mia40 knockdown/overexpression, immunofluorescence localization, cycloheximide stability assay","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis plus mechanistic rescue experiment, multiple mutants tested","pmids":["29789341"],"is_preprint":false},{"year":2018,"finding":"CHCHD2 and CHCHD10 form heterodimers that increase in response to mitochondrial stress; CHCHD2 is preferentially stabilized upon loss of mitochondrial membrane potential, and CHCHD10 oligomerization depends on CHCHD2 expression; disease-causing mutations in both proteins can be incorporated into heterodimers.","method":"CHCHD2/CHCHD10 double-knockout cell lines, co-immunoprecipitation, immunofluorescence, CCCP treatment, heterodimer incorporation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with knockout controls, multiple orthogonal methods","pmids":["30084972"],"is_preprint":false},{"year":2018,"finding":"CHCHD10 copurifies with cytochrome c oxidase (Complex IV) and up-regulates COX activity by acting as a scaffolding protein required for MNRR1/CHCHD2 phosphorylation mediated by ABL2 kinase; nuclear CHCHD10 interacts with the transcriptional repressor CXXC5 and down-regulates expression of genes with oxygen-responsive elements (ORE) in their promoters; disease variants G66V and P80L exhibit faulty interactions with MNRR1 and COX, reducing respiration and increasing ROS.","method":"Co-purification/Co-IP with COX, COX activity assay, nuclear fractionation, reporter gene assay, ROS measurement, Seahorse bioenergetics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical co-purification with enzymatic activity assay, nuclear interaction with functional readout, disease mutants tested","pmids":["29540477"],"is_preprint":false},{"year":2019,"finding":"CHCHD10 S55L (mouse equivalent of human S59L) knock-in mice accumulate CHCHD10/CHCHD2 aggregates specifically in affected tissues, leading to aberrant organelle morphology and activation of a mitochondrial integrated stress response (mtISR) through mTORC1; CHCHD10 ablation does not induce disease pathology or activate mtISR, indicating that S55L disease is caused by a toxic gain-of-function rather than loss-of-function.","method":"Knock-in mouse model, protein aggregation analysis (fractionation/IF), electron microscopy, transcriptomic/metabolomic profiling, mTORC1 pathway analysis, CHCHD10 knockout comparison","journal":"Acta neuropathologica","confidence":"High","confidence_rationale":"Tier 2 — knock-in vs. knockout genetic comparison, multiple orthogonal readouts, rigorous controls","pmids":["30877432"],"is_preprint":false},{"year":2020,"finding":"Loss of both CHCHD2 and CHCHD10 (double knockout mice) disrupts mitochondrial cristae through OMA1-mediated cleavage of long-form OPA1 (L-OPA1); OMA1 is similarly activated in affected tissues of mutant CHCHD10 knock-in mice; C2/C10 DKO mice develop cardiomyopathy and activate the mtISR, partially phenocopying mutant C10 KI mice.","method":"CHCHD2/CHCHD10 double-knockout mice, OMA1 activation assay, OPA1 cleavage by western blot, electron microscopy, knock-in mouse comparison","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — double-KO mice with mechanistic identification of OMA1-OPA1 pathway, confirmed in KI model","pmids":["32338760"],"is_preprint":false},{"year":2022,"finding":"CHCHD2 and CHCHD10 interact with OMA1 and suppress its protease activity under physiological conditions, restraining both mtISR initiation and OPA1 processing for mitochondrial fusion; during mitochondrial stress (CCCP), CHCHD2 and CHCHD10 translocate to the cytosol and interact with eIF2α, attenuating mtISR overactivation by suppressing eIF2α phosphorylation.","method":"Co-immunoprecipitation with OMA1, OPA1 cleavage assay, CCCP treatment, cytosol/mitochondria fractionation, eIF2α phosphorylation measurement, CHCHD2/CHCHD10 knockdown","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — direct Co-IP identifying OMA1 as interactor/substrate, functional enzyme activity assay, multiple orthogonal methods","pmids":["35173147"],"is_preprint":false},{"year":2022,"finding":"OMA1 mediates a protective stress response in CHCHD10 G58R mutant knock-in mice by acting both locally (mitochondrial fragmentation) and globally (cleavage of DELE1 to activate the integrated stress response); survival of CHCHD10-KI mice depends on this OMA1-mediated response; an isoform switch in the terminal complex of the electron transport chain also occurs as part of this response.","method":"Knock-in mouse model, OMA1 knockout cross, DELE1 cleavage assay, electron microscopy, transcriptomic profiling","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (OMA1 KO in KI background) with defined survival phenotype and mechanistic pathway identification","pmids":["35700042"],"is_preprint":false},{"year":2022,"finding":"CHCHD10 interacts with SLP2 (Stomatin-Like Protein 2) and participates in the stability of the prohibitin (PHB) complex in the inner mitochondrial membrane; CHCHD10 S59L mutation causes SLP2 and prohibitins to form aggregates, destabilizing the PHB complex, which activates OMA1 leading to OPA1 processing, mitochondrial fragmentation, and neuronal death; this also destabilizes the MICOS complex through disruption of OPA1-mitofilin interaction.","method":"Co-immunoprecipitation, patient fibroblasts and knock-in mouse tissue analysis, immunofluorescence, electron microscopy, OPA1 cleavage assay","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifying new interactor SLP2/PHB, functional cascade validated in patient cells and mouse model","pmids":["35656794"],"is_preprint":false},{"year":2019,"finding":"CHCHD10 is highly expressed at the postsynaptic NMJ in skeletal muscle; muscle-conditional CHCHD10 knockout mice exhibit motor defects, abnormal neuromuscular transmission, and disrupted NMJ structure; mechanistically, CHCHD10 is required for mitochondrial ATP production, which facilitates AChR expression and promotes agrin-induced AChR clustering; exogenous ATP rescues AChR cluster reduction.","method":"Muscle-conditional knockout mice, electrophysiology, AChR clustering assay, ATP rescue experiment, immunofluorescence","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined cellular mechanism (ATP-AChR axis) and functional rescue","pmids":["31261376"],"is_preprint":false},{"year":2017,"finding":"CHCHD10 normally promotes retention of nuclear TDP-43, protects mitochondrial and synaptic integrity; FTD/ALS mutations R15L and S59L exhibit loss-of-function phenotypes in C. elegans genetic complementation assays and dominant-negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation.","method":"C. elegans genetic complementation assay, mammalian cell overexpression, primary neurons, mouse brain analysis, TDP-43 localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in C. elegans plus mammalian cell functional assays, multiple model systems","pmids":["28585542"],"is_preprint":false},{"year":2021,"finding":"The p.R15L CHCHD10 variant (haploinsufficient) causes Complex I deficiency resulting in elevated NADH/NAD+ ratio, diminished TCA cycle activity, reorganization of one-carbon metabolism, increased AMP/ATP ratio leading to AMPK phosphorylation and mTORC1 inhibition; these metabolic changes activate UPR in the ER (IRE1/XBP1 pathway) and the mitochondrial UPR through ATF4/ATF5 upregulation.","method":"Multi-OMICS (transcriptomics, metabolomics, proteomics) in patient fibroblasts under energetic stress, pathway analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multi-OMICS integration with orthogonal pathway validation, rigorous energetic stress paradigm","pmids":["33749723"],"is_preprint":false},{"year":2019,"finding":"CHCHD10 S59L knock-in mice develop OXPHOS deficiency in muscle at 3 months before neuromuscular junction degeneration and motor neuron loss, establishing that muscle pathology precedes neurodegeneration; TDP-43 cytoplasmic aggregates appear in spinal neurons at late disease stage; iPSC-derived motor neurons with S59L are more sensitive to caspase activation.","method":"Knock-in mouse model, histochemistry (OXPHOS), NMJ morphology, motor neuron counting, TDP-43 immunostaining, iPSC-derived motor neuron caspase assay","journal":"Acta neuropathologica","confidence":"High","confidence_rationale":"Tier 2 — temporal epistasis in KI model with multiple tissue readouts, iPSC validation","pmids":["30874923"],"is_preprint":false},{"year":2021,"finding":"In Drosophila and HeLa cells, CHCHD10 S59L independently activates the TDP-43 and PINK1 pathways: S59L increases TDP-43 insolubility and mitochondrial translocation; blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduces S59L-mediated toxicity; genetic and pharmacological modulation of PINK1 rescues S59L-induced phenotypes.","method":"Drosophila transgenic model, HeLa cell overexpression, peptide inhibitor of TDP-43 import, PINK1 genetic and pharmacological modulation, mitochondrial fractionation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in two model systems, pharmacological rescue, multiple orthogonal readouts","pmids":["33772006"],"is_preprint":false},{"year":2020,"finding":"CHCHD10 mutations disrupt mitochondrial OPA1-mitofilin complexes in brain, impairing mitochondrial fusion and respiration; CHCHD10 knockdown causes OPA1-mitofilin complex disassembly; TDP-43 overexpression reduces CHCHD10 levels and promotes OPA1-mitofilin disassembly via CHCHD10, and WT CHCHD10 overexpression rescues these defects.","method":"Co-immunoprecipitation, CHCHD10 knockdown/overexpression, mitochondrial fusion assay, Seahorse respiration, FTLD-TDP patient brain analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional rescue, validated in patient brain tissue","pmids":["32369233"],"is_preprint":false},{"year":2023,"finding":"CHCHD10 normally interacts with PARL, suppressing its activity, which sustains PINK1 levels and promotes mitophagy flux and Parkin recruitment; CHCHD10 R15L and S59L mutations reduce PINK1 levels by increasing PARL activity; impaired mitophagy promotes TDP-43 aggregation.","method":"Co-immunoprecipitation with PARL, PINK1 level measurement, mitophagy flux assay, Parkin recruitment assay, in vivo mouse and human FTD brain tissue","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifying PARL as interactor with functional consequence, validated in multiple in vivo and in vitro systems","pmids":["38132101"],"is_preprint":false},{"year":2018,"finding":"CHCHD10 G66V and P80L mutations cause motoneuron disease primarily through haploinsufficiency: p.R15L reduces CHCHD10 mRNA expression, while p.G66V results in altered protein secondary structure and rapid degradation, reducing protein levels to ~50%; knockdown of CHCHD10 to ~50% in zebrafish causes motoneuron pathology, abnormal myofibrillar structure, and motility deficits.","method":"Patient cell protein/mRNA quantification, secondary structure analysis, zebrafish knockdown model, motor behavior assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic dose-response in zebrafish with defined phenotype, patient cell biochemistry","pmids":["29315381"],"is_preprint":false},{"year":2022,"finding":"CHCHD10 S59L mutant protein induces aggregation of resident CHCHD10 and promotes aggregation and slower turnover of imported TDP-43 in isolated mitochondria; in a cell-free system, S59L CHCHD10 enhances TDP-43 aggregation while WT CHCHD10 inhibits TDP-43 aggregate growth, as shown by filter trap assay and atomic force microscopy.","method":"Isolated mitochondria import assay, cell-free aggregation assay, filter trap, atomic force microscopy, transgenic mouse brain analysis","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution (cell-free system and isolated mitochondria) with multiple orthogonal structural assays","pmids":["35787294"],"is_preprint":false},{"year":2025,"finding":"Mutant CHCHD10 (S55L/S59L) causes dual defects: (1) impaired mitochondrial copper homeostasis leading to defective cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis; defective respiration in mutant mitochondria is rescued by exogenous addition of cytochrome c, implicating IMS proteostasis disruption as a key pathogenic mechanism; blunting OMA1 activity (Oma1 E324Q KI) delays cardiomyopathy without rescuing OXPHOS impairment.","method":"Knock-in mouse models, proteomic profiling (soluble/insoluble fractions), cytochrome c rescue of respiration, OMA1 catalytic mutant cross, DELE1 cleavage assay","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 — cytochrome c biochemical rescue identifies specific mechanism, OMA1 epistasis dissects pathway, multiple orthogonal methods","pmids":["41420107"],"is_preprint":false},{"year":2022,"finding":"CHCHD10 deficiency in adipocytes disrupts mitochondrial cristae and OXPHOS complex assembly, impairing ATP generation; decreased ATP reduces lipolysis by lowering nascent ATGL protein synthesis, thereby suppressing UCP1-dependent thermogenesis; ATGL overexpression rescues thermogenesis in CHCHD10-knockout adipocytes.","method":"Adipocyte-specific CHCHD10 knockout mice, UCP1/ATP measurement, lipolysis assay, ATGL overexpression rescue, Seahorse bioenergetics","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined mechanistic rescue (ATGL overexpression), multiple orthogonal readouts","pmids":["35709007"],"is_preprint":false},{"year":2019,"finding":"CHCHD2 T61I mutation causes increased interaction between CHCHD2 and CHCHD10, leading to reduced CHCHD10 levels; mitochondrial ultrastructural alterations in CHCHD2 T61I patient fibroblasts resemble those of CHCHD10 mutation cells.","method":"Co-immunoprecipitation, CHCHD10 protein level measurement, patient fibroblast electron microscopy","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with protein level measurement, single lab","pmids":["30530185"],"is_preprint":false},{"year":2024,"finding":"The N-terminal disordered domain of CHCHD10 forms amyloid fibrils whose cryo-EM structure shows that disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining their co-aggregation.","method":"CryoEM structure determination, amyloid fibril formation assay, mutant accommodation modeling","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 — cryo-EM structure, but preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"CHCHD2 and CHCHD10 exist in mouse tissues as a high molecular weight complex whose levels increase in response to mitochondrial dysfunction; loss of CHCHD2 enhances cellular vulnerability to mitochondrial stress; CHCHD2 is required for normal striatal dopamine levels and lipid homeostasis in mouse brain.","method":"Chchd2 knockout mouse, BN-PAGE complex analysis, mitochondrial stress treatments, dopamine measurement, lipidomics","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with BN-PAGE complex identification, single lab","pmids":["41053020"],"is_preprint":false},{"year":2023,"finding":"Loss of chchd10 (but not chchd2) in zebrafish impairs assembly of mitochondrial respiratory Complex I; in double chchd10/chchd2 knockout zebrafish, Complex I impairment is unexpectedly restored via mtISR transcriptional activation, showing that the mt-ISR can compensate for Complex I deficiency.","method":"Zebrafish knockout models (single and double), Complex I assembly BN-PAGE, mt-ISR transcriptional markers, motor behavior assay","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in vertebrate model, BN-PAGE complex assembly assay, single lab","pmids":["36799027"],"is_preprint":false},{"year":2025,"finding":"CHCHD10 deficiency in adipose tissue enhances adipogenesis and GSTA4 expression by activating a TDP43/Raptor/p62/Keap1/NRF2 axis; in hypertrophic adipocytes where p62 is reduced, this beneficial effect is eliminated.","method":"AT-specific Chchd10 KO mice, co-IP/pathway analysis, p62 manipulation, NRF2 reporter assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with pathway identification, single lab","pmids":["39985288"],"is_preprint":false}],"current_model":"CHCHD10 is a mitochondrial intermembrane space protein that, as part of the MICOS complex (with mitofilin/CHCHD3/CHCHD6), maintains cristae junction integrity and mitochondrial DNA stability; it forms heterodimers with its paralog CHCHD2 and interacts with Complex IV/COX, the prohibitin complex, SLP2, OMA1, PARL, and p32/C1QBP to regulate OXPHOS, cristae morphology, mtISR, mitophagy flux (via the PARL-PINK1 axis), and TDP-43 nuclear retention, with pathogenic mutations acting primarily through a toxic gain-of-function mechanism—protein misfolding/aggregation that disrupts IMS proteostasis, triggers aberrant OMA1-DELE1-HRI signaling, and impairs cytochrome c biogenesis."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing that CHCHD10 participates in oxidative phosphorylation answered the basic question of what this uncharacterized CHCH-domain protein does: it is required for Complex IV activity.","evidence":"siRNA knockdown with Complex IV activity assay in vitro","pmids":["20888800"],"confidence":"Medium","gaps":["Single lab, single complex assayed","No mechanism for how CHCHD10 supports Complex IV identified","Broader OXPHOS roles not tested"]},{"year":2014,"claim":"Localization of CHCHD10 to the intermembrane space at cristae junctions and demonstration that the S59L mutation disrupts cristae established the protein as a structural organizer of mitochondrial inner membrane architecture and linked it to FTD-ALS.","evidence":"Immunofluorescence, subcellular fractionation, and electron microscopy of S59L-overexpressing HeLa cells; genetic linkage in FTD-ALS family","pmids":["24934289"],"confidence":"High","gaps":["Endogenous complex membership not yet identified","Whether loss-of-function or gain-of-function drives disease was unknown"]},{"year":2016,"claim":"Identification of CHCHD10 as a component of the MICOS complex (with mitofilin, CHCHD3, CHCHD6) explained how it organizes cristae junctions and revealed that disease mutations cause MICOS disassembly, nucleoid loss, and impaired mtDNA repair.","evidence":"Co-immunoprecipitation in patient fibroblasts, electron microscopy, nucleoid staining, cytochrome c release assay","pmids":["26666268"],"confidence":"High","gaps":["Direct structural contacts within MICOS not resolved","Whether CHCHD10 is a core or peripheral MICOS subunit unclear"]},{"year":2017,"claim":"Demonstration that CHCHD10 promotes nuclear retention of TDP-43 and that disease mutations cause cytoplasmic TDP-43 mislocalization connected mitochondrial dysfunction to a hallmark of ALS/FTD pathology.","evidence":"C. elegans genetic complementation, mammalian cell overexpression, primary neuron and mouse brain TDP-43 localization","pmids":["28585542"],"confidence":"High","gaps":["Mechanism by which CHCHD10 retains TDP-43 in the nucleus not identified","Whether TDP-43 mislocalization is a cause or consequence of mitochondrial damage unclear"]},{"year":2018,"claim":"Multiple studies converged to define CHCHD10's molecular partnerships and biogenesis: it forms heterodimers with CHCHD2 in a stress-responsive ~220 kDa complex, interacts with p32/C1QBP, scaffolds COX activity via CHCHD2/ABL2, and requires Mia40-dependent disulfide bond formation for mitochondrial import; disease mutations disrupt these interactions through distinct mechanisms (import failure, destabilization, or aberrant binding).","evidence":"Co-IP/MS interactome, BN-PAGE, COX co-purification and activity assay, Mia40 knockdown/rescue, truncation mutagenesis, zebrafish knockdown, patient fibroblasts, multiple disease mutants tested across labs","pmids":["29112723","29121267","29540477","30084972","29789341","29315381"],"confidence":"High","gaps":["Stoichiometry of the ~220 kDa complex not determined","Whether nuclear CHCHD10-CXXC5 interaction is physiologically significant in vivo unclear","Structural basis of heterodimer formation unknown"]},{"year":2019,"claim":"Comparison of S55L knock-in versus CHCHD10-knockout mice resolved the disease mechanism debate: mutant protein aggregates activate mtISR via mTORC1 in a toxic gain-of-function manner, while knockout alone does not cause neurodegeneration; separately, muscle-conditional knockout revealed that CHCHD10 maintains neuromuscular junction integrity through ATP-dependent AChR clustering.","evidence":"Knock-in vs. knockout mouse comparison, aggregation analysis, transcriptomics/metabolomics, muscle-conditional KO with electrophysiology and ATP rescue","pmids":["30877432","31261376","30874923"],"confidence":"High","gaps":["Why aggregate toxicity is tissue-selective not explained","Whether gain-of-function and haploinsufficiency mechanisms coexist for different mutations not fully resolved"]},{"year":2020,"claim":"Identification of OMA1-mediated L-OPA1 cleavage as the effector of cristae disruption in CHCHD2/CHCHD10 double-knockout mice provided the first enzymatic mechanism linking CHCHD10 loss to mitochondrial fragmentation, and revealed that TDP-43 overexpression itself reduces CHCHD10 levels to disrupt OPA1-mitofilin complexes.","evidence":"CHCHD2/CHCHD10 double-KO mice, OMA1 activation and OPA1 cleavage assays, Co-IP in FTLD-TDP patient brain, CHCHD10 overexpression rescue","pmids":["32338760","32369233"],"confidence":"High","gaps":["How CHCHD10 inhibits OMA1 at the molecular level unknown","Whether OPA1-mitofilin disruption is the primary driver or one of several parallel cascades uncertain"]},{"year":2021,"claim":"Multi-omics of R15L patient fibroblasts revealed that Complex I deficiency drives a metabolic cascade (elevated NADH/NAD+, AMPK activation, mTORC1 inhibition, UPR activation), while Drosophila/cell studies showed that S59L activates TDP-43 and PINK1 pathways independently, with pharmacological PINK1 modulation providing rescue.","evidence":"Integrated transcriptomics/metabolomics/proteomics in patient fibroblasts, Drosophila transgenic model with PINK1 genetic/pharmacological epistasis, TDP-43 mitochondrial import inhibitor peptide","pmids":["33749723","33772006"],"confidence":"High","gaps":["Whether PINK1 pathway activation is protective or pathogenic across all mutation types not established","Therapeutic potential of TDP-43 import inhibition not tested in mammalian models"]},{"year":2022,"claim":"The OMA1–DELE1–HRI signaling axis was identified as both a pathogenic output and a protective response in CHCHD10 disease: CHCHD10/CHCHD2 normally suppress OMA1 and cytosolic eIF2α phosphorylation, while OMA1-dependent DELE1 cleavage is required for survival of G58R knock-in mice; simultaneously, S59L aggregates destabilize the SLP2-prohibitin complex upstream of OMA1, and WT CHCHD10 directly inhibits TDP-43 aggregation in reconstituted systems.","evidence":"Co-IP with OMA1 and SLP2/PHB, OMA1 KO genetic cross in KI mice, DELE1 cleavage assay, eIF2α phosphorylation, cell-free TDP-43 aggregation with atomic force microscopy","pmids":["35173147","35700042","35656794","35787294"],"confidence":"High","gaps":["Whether OMA1 suppression and mtISR attenuation are independent or sequential functions of CHCHD10 not resolved","Direct binding interface between CHCHD10 and OMA1 not structurally defined"]},{"year":2023,"claim":"Discovery that CHCHD10 interacts with PARL to suppress its protease activity, thereby sustaining PINK1 for mitophagy, provided the mechanistic link between CHCHD10 mutations and impaired mitophagy flux that promotes TDP-43 aggregation.","evidence":"Co-IP with PARL, PINK1 level measurement, mitophagy flux and Parkin recruitment assays in mouse and human FTD brain","pmids":["38132101"],"confidence":"High","gaps":["Whether PARL interaction is direct or mediated through the PHB/SLP2 platform not determined","Relative contribution of impaired mitophagy vs. direct aggregation to TDP-43 pathology unclear"]},{"year":2025,"claim":"The pathogenic cascade was further refined: mutant CHCHD10 disrupts IMS copper homeostasis and cytochrome c biogenesis, and exogenous cytochrome c rescues respiration, pinpointing IMS proteostasis failure as a proximal cause; OMA1 catalytic blunting delays cardiomyopathy but does not rescue OXPHOS, separating the stress-signaling and bioenergetic arms of disease.","evidence":"Knock-in mouse proteomic profiling, cytochrome c biochemical rescue of respiration, OMA1 E324Q catalytic mutant cross","pmids":["41420107"],"confidence":"High","gaps":["How mutant CHCHD10 specifically impairs copper delivery or cytochrome c maturation not resolved","Whether IMS proteostasis disruption is reversible therapeutically not tested"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of the CHCHD10-CHCHD2 heterodimer and its interfaces with OMA1, PARL, and MICOS components; the basis for tissue-selective vulnerability in gain-of-function disease; and whether therapeutic strategies targeting OMA1, PINK1, or TDP-43 mitochondrial import can modify disease course in mammalian models.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the CHCHD10-CHCHD2 complex or its interaction interfaces","Tissue-selective vulnerability mechanism unexplained","No preclinical therapeutic efficacy data in mammalian ALS/FTD models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,11,19]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,7,12]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,3,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,4,7,15,22,23]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,10,11,15,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[19]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,9,12]}],"complexes":["MICOS complex","CHCHD10-CHCHD2 heterodimer","SLP2-prohibitin complex"],"partners":["CHCHD2","IMMT","CHCHD3","CHCHD6","C1QBP","SLP2","OMA1","PARL"],"other_free_text":[]},"mechanistic_narrative":"CHCHD10 is a mitochondrial intermembrane space protein that maintains cristae architecture, oxidative phosphorylation, and mitochondrial DNA stability by functioning within the MICOS complex and as a heterodimer with its paralog CHCHD2. It interacts with cytochrome c oxidase (Complex IV) to scaffold COX activity, suppresses OMA1 protease activity to preserve long-form OPA1 and cristae junctions, and interacts with PARL to sustain PINK1-dependent mitophagy flux; during mitochondrial stress, CHCHD10 translocates to the cytosol to attenuate integrated stress response signaling by suppressing eIF2α phosphorylation [PMID:26666268, PMID:35173147, PMID:29540477, PMID:38132101]. Disease-associated mutations (e.g., S59L, R15L, G58R) act primarily through toxic gain-of-function aggregation that disrupts IMS proteostasis, activates the OMA1–DELE1–HRI stress axis, impairs cytochrome c biogenesis, and promotes cytoplasmic TDP-43 mislocalization, whereas complete loss of CHCHD10 alone does not recapitulate disease but impairs Complex I assembly and ATP-dependent processes including neuromuscular junction maintenance and adipocyte thermogenesis [PMID:30877432, PMID:35700042, PMID:41420107, PMID:31261376, PMID:35709007]. Mutations in CHCHD10 cause frontotemporal dementia–amyotrophic lateral sclerosis spectrum disease and motor neuron disease [PMID:24934289, PMID:29315381]."},"prefetch_data":{"uniprot":{"accession":"Q8WYQ3","full_name":"Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial","aliases":["Protein N27C7-4"],"length_aa":142,"mass_kda":14.1,"function":"May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure","subcellular_location":"Mitochondrion intermembrane space","url":"https://www.uniprot.org/uniprotkb/Q8WYQ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHCHD10","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHCHD10","total_profiled":1310},"omim":[{"mim_id":"616209","title":"MYOPATHY, ISOLATED MITOCHONDRIAL, AUTOSOMAL DOMINANT; 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Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/32651855","citation_count":0,"is_preprint":false},{"pmid":"40452868","id":"PMC_40452868","title":"har-1/CHCHD10 mutations induce neurodegeneration and mitochondrial fragmentation in Caenorhabditis elegans.","date":"2025","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/40452868","citation_count":0,"is_preprint":false},{"pmid":"38895204","id":"PMC_38895204","title":"FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 .","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38895204","citation_count":0,"is_preprint":false},{"pmid":"41633268","id":"PMC_41633268","title":"A FEN1-EDCR dual-amplification strategy for ultrasensitive detection of CHCHD10 c.176C>T mutation.","date":"2026","source":"Biosensors & 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microscopy, overexpression of mutant allele in HeLa cells\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, replicated across labs\",\n      \"pmids\": [\"24934289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHCHD10 resides within the MICOS (mitochondrial contact site and cristae organizing system) complex together with mitofilin, CHCHD3, and CHCHD6; disease-associated CHCHD10 mutations lead to MICOS complex disassembly, loss of cristae, decreased nucleoid number, impaired mtDNA repair after oxidative stress, and inhibition of apoptosis by preventing cytochrome c release.\",\n      \"method\": \"Co-immunoprecipitation, patient fibroblast analysis, electron microscopy, nucleoid staining, cytochrome c release assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying complex membership, multiple orthogonal functional assays, replicated in patient cells\",\n      \"pmids\": [\"26666268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHCHD10 knockdown reduces Complex IV (cytochrome c oxidase) activity in vitro, establishing a role for CHCHD10 in oxidative phosphorylation.\",\n      \"method\": \"siRNA knockdown, complex IV activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro activity assay, single lab\",\n      \"pmids\": [\"20888800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHCHD10 associates with membranes in the mitochondrial intermembrane space and directly interacts with its paralog CHCHD2 and with p32/C1QBP; CHCHD10 has a short half-life suggesting a regulatory role; knockdown leads to intramitochondrial iron accumulation; S59L and R15L mutants (but not WT) impair mitochondrial energy metabolism.\",\n      \"method\": \"Immunoprecipitation/MS interactome, subcellular fractionation, pulse-chase half-life assays, iron measurement, Seahorse bioenergetics, knockout mice\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"29112723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The p.R15L CHCHD10 variant destabilizes the protein and causes defective assembly of mitochondrial Complex I, impaired cellular respiration, and mitochondrial hyperfusion; CHCHD10 and CHCHD2 form a high molecular weight complex (~220 kDa) by blue native PAGE that is absent in patient cells.\",\n      \"method\": \"Blue native PAGE, immunoprecipitation, oxygen consumption measurement, patient fibroblasts, galactose growth assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — BN-PAGE complex identification plus functional respiration assay in patient cells\",\n      \"pmids\": [\"29121267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the N-terminal targeting signal and depends on Mia40, which introduces disulfide bonds; the Q108P disease mutation nearly completely blocks mitochondrial import, resulting in cytoplasmic mislocalization; Mia40 overexpression rescues import of CHCHD10 Q108P.\",\n      \"method\": \"Truncation mutagenesis, Mia40 knockdown/overexpression, immunofluorescence localization, cycloheximide stability assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis plus mechanistic rescue experiment, multiple mutants tested\",\n      \"pmids\": [\"29789341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHCHD2 and CHCHD10 form heterodimers that increase in response to mitochondrial stress; CHCHD2 is preferentially stabilized upon loss of mitochondrial membrane potential, and CHCHD10 oligomerization depends on CHCHD2 expression; disease-causing mutations in both proteins can be incorporated into heterodimers.\",\n      \"method\": \"CHCHD2/CHCHD10 double-knockout cell lines, co-immunoprecipitation, immunofluorescence, CCCP treatment, heterodimer incorporation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with knockout controls, multiple orthogonal methods\",\n      \"pmids\": [\"30084972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHCHD10 copurifies with cytochrome c oxidase (Complex IV) and up-regulates COX activity by acting as a scaffolding protein required for MNRR1/CHCHD2 phosphorylation mediated by ABL2 kinase; nuclear CHCHD10 interacts with the transcriptional repressor CXXC5 and down-regulates expression of genes with oxygen-responsive elements (ORE) in their promoters; disease variants G66V and P80L exhibit faulty interactions with MNRR1 and COX, reducing respiration and increasing ROS.\",\n      \"method\": \"Co-purification/Co-IP with COX, COX activity assay, nuclear fractionation, reporter gene assay, ROS measurement, Seahorse bioenergetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical co-purification with enzymatic activity assay, nuclear interaction with functional readout, disease mutants tested\",\n      \"pmids\": [\"29540477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHCHD10 S55L (mouse equivalent of human S59L) knock-in mice accumulate CHCHD10/CHCHD2 aggregates specifically in affected tissues, leading to aberrant organelle morphology and activation of a mitochondrial integrated stress response (mtISR) through mTORC1; CHCHD10 ablation does not induce disease pathology or activate mtISR, indicating that S55L disease is caused by a toxic gain-of-function rather than loss-of-function.\",\n      \"method\": \"Knock-in mouse model, protein aggregation analysis (fractionation/IF), electron microscopy, transcriptomic/metabolomic profiling, mTORC1 pathway analysis, CHCHD10 knockout comparison\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in vs. knockout genetic comparison, multiple orthogonal readouts, rigorous controls\",\n      \"pmids\": [\"30877432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of both CHCHD2 and CHCHD10 (double knockout mice) disrupts mitochondrial cristae through OMA1-mediated cleavage of long-form OPA1 (L-OPA1); OMA1 is similarly activated in affected tissues of mutant CHCHD10 knock-in mice; C2/C10 DKO mice develop cardiomyopathy and activate the mtISR, partially phenocopying mutant C10 KI mice.\",\n      \"method\": \"CHCHD2/CHCHD10 double-knockout mice, OMA1 activation assay, OPA1 cleavage by western blot, electron microscopy, knock-in mouse comparison\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double-KO mice with mechanistic identification of OMA1-OPA1 pathway, confirmed in KI model\",\n      \"pmids\": [\"32338760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHCHD2 and CHCHD10 interact with OMA1 and suppress its protease activity under physiological conditions, restraining both mtISR initiation and OPA1 processing for mitochondrial fusion; during mitochondrial stress (CCCP), CHCHD2 and CHCHD10 translocate to the cytosol and interact with eIF2α, attenuating mtISR overactivation by suppressing eIF2α phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation with OMA1, OPA1 cleavage assay, CCCP treatment, cytosol/mitochondria fractionation, eIF2α phosphorylation measurement, CHCHD2/CHCHD10 knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP identifying OMA1 as interactor/substrate, functional enzyme activity assay, multiple orthogonal methods\",\n      \"pmids\": [\"35173147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OMA1 mediates a protective stress response in CHCHD10 G58R mutant knock-in mice by acting both locally (mitochondrial fragmentation) and globally (cleavage of DELE1 to activate the integrated stress response); survival of CHCHD10-KI mice depends on this OMA1-mediated response; an isoform switch in the terminal complex of the electron transport chain also occurs as part of this response.\",\n      \"method\": \"Knock-in mouse model, OMA1 knockout cross, DELE1 cleavage assay, electron microscopy, transcriptomic profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (OMA1 KO in KI background) with defined survival phenotype and mechanistic pathway identification\",\n      \"pmids\": [\"35700042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHCHD10 interacts with SLP2 (Stomatin-Like Protein 2) and participates in the stability of the prohibitin (PHB) complex in the inner mitochondrial membrane; CHCHD10 S59L mutation causes SLP2 and prohibitins to form aggregates, destabilizing the PHB complex, which activates OMA1 leading to OPA1 processing, mitochondrial fragmentation, and neuronal death; this also destabilizes the MICOS complex through disruption of OPA1-mitofilin interaction.\",\n      \"method\": \"Co-immunoprecipitation, patient fibroblasts and knock-in mouse tissue analysis, immunofluorescence, electron microscopy, OPA1 cleavage assay\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying new interactor SLP2/PHB, functional cascade validated in patient cells and mouse model\",\n      \"pmids\": [\"35656794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHCHD10 is highly expressed at the postsynaptic NMJ in skeletal muscle; muscle-conditional CHCHD10 knockout mice exhibit motor defects, abnormal neuromuscular transmission, and disrupted NMJ structure; mechanistically, CHCHD10 is required for mitochondrial ATP production, which facilitates AChR expression and promotes agrin-induced AChR clustering; exogenous ATP rescues AChR cluster reduction.\",\n      \"method\": \"Muscle-conditional knockout mice, electrophysiology, AChR clustering assay, ATP rescue experiment, immunofluorescence\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular mechanism (ATP-AChR axis) and functional rescue\",\n      \"pmids\": [\"31261376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHCHD10 normally promotes retention of nuclear TDP-43, protects mitochondrial and synaptic integrity; FTD/ALS mutations R15L and S59L exhibit loss-of-function phenotypes in C. elegans genetic complementation assays and dominant-negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation.\",\n      \"method\": \"C. elegans genetic complementation assay, mammalian cell overexpression, primary neurons, mouse brain analysis, TDP-43 localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in C. elegans plus mammalian cell functional assays, multiple model systems\",\n      \"pmids\": [\"28585542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The p.R15L CHCHD10 variant (haploinsufficient) causes Complex I deficiency resulting in elevated NADH/NAD+ ratio, diminished TCA cycle activity, reorganization of one-carbon metabolism, increased AMP/ATP ratio leading to AMPK phosphorylation and mTORC1 inhibition; these metabolic changes activate UPR in the ER (IRE1/XBP1 pathway) and the mitochondrial UPR through ATF4/ATF5 upregulation.\",\n      \"method\": \"Multi-OMICS (transcriptomics, metabolomics, proteomics) in patient fibroblasts under energetic stress, pathway analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-OMICS integration with orthogonal pathway validation, rigorous energetic stress paradigm\",\n      \"pmids\": [\"33749723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHCHD10 S59L knock-in mice develop OXPHOS deficiency in muscle at 3 months before neuromuscular junction degeneration and motor neuron loss, establishing that muscle pathology precedes neurodegeneration; TDP-43 cytoplasmic aggregates appear in spinal neurons at late disease stage; iPSC-derived motor neurons with S59L are more sensitive to caspase activation.\",\n      \"method\": \"Knock-in mouse model, histochemistry (OXPHOS), NMJ morphology, motor neuron counting, TDP-43 immunostaining, iPSC-derived motor neuron caspase assay\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — temporal epistasis in KI model with multiple tissue readouts, iPSC validation\",\n      \"pmids\": [\"30874923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila and HeLa cells, CHCHD10 S59L independently activates the TDP-43 and PINK1 pathways: S59L increases TDP-43 insolubility and mitochondrial translocation; blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduces S59L-mediated toxicity; genetic and pharmacological modulation of PINK1 rescues S59L-induced phenotypes.\",\n      \"method\": \"Drosophila transgenic model, HeLa cell overexpression, peptide inhibitor of TDP-43 import, PINK1 genetic and pharmacological modulation, mitochondrial fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in two model systems, pharmacological rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"33772006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHCHD10 mutations disrupt mitochondrial OPA1-mitofilin complexes in brain, impairing mitochondrial fusion and respiration; CHCHD10 knockdown causes OPA1-mitofilin complex disassembly; TDP-43 overexpression reduces CHCHD10 levels and promotes OPA1-mitofilin disassembly via CHCHD10, and WT CHCHD10 overexpression rescues these defects.\",\n      \"method\": \"Co-immunoprecipitation, CHCHD10 knockdown/overexpression, mitochondrial fusion assay, Seahorse respiration, FTLD-TDP patient brain analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional rescue, validated in patient brain tissue\",\n      \"pmids\": [\"32369233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHCHD10 normally interacts with PARL, suppressing its activity, which sustains PINK1 levels and promotes mitophagy flux and Parkin recruitment; CHCHD10 R15L and S59L mutations reduce PINK1 levels by increasing PARL activity; impaired mitophagy promotes TDP-43 aggregation.\",\n      \"method\": \"Co-immunoprecipitation with PARL, PINK1 level measurement, mitophagy flux assay, Parkin recruitment assay, in vivo mouse and human FTD brain tissue\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying PARL as interactor with functional consequence, validated in multiple in vivo and in vitro systems\",\n      \"pmids\": [\"38132101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHCHD10 G66V and P80L mutations cause motoneuron disease primarily through haploinsufficiency: p.R15L reduces CHCHD10 mRNA expression, while p.G66V results in altered protein secondary structure and rapid degradation, reducing protein levels to ~50%; knockdown of CHCHD10 to ~50% in zebrafish causes motoneuron pathology, abnormal myofibrillar structure, and motility deficits.\",\n      \"method\": \"Patient cell protein/mRNA quantification, secondary structure analysis, zebrafish knockdown model, motor behavior assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic dose-response in zebrafish with defined phenotype, patient cell biochemistry\",\n      \"pmids\": [\"29315381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHCHD10 S59L mutant protein induces aggregation of resident CHCHD10 and promotes aggregation and slower turnover of imported TDP-43 in isolated mitochondria; in a cell-free system, S59L CHCHD10 enhances TDP-43 aggregation while WT CHCHD10 inhibits TDP-43 aggregate growth, as shown by filter trap assay and atomic force microscopy.\",\n      \"method\": \"Isolated mitochondria import assay, cell-free aggregation assay, filter trap, atomic force microscopy, transgenic mouse brain analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution (cell-free system and isolated mitochondria) with multiple orthogonal structural assays\",\n      \"pmids\": [\"35787294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mutant CHCHD10 (S55L/S59L) causes dual defects: (1) impaired mitochondrial copper homeostasis leading to defective cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis; defective respiration in mutant mitochondria is rescued by exogenous addition of cytochrome c, implicating IMS proteostasis disruption as a key pathogenic mechanism; blunting OMA1 activity (Oma1 E324Q KI) delays cardiomyopathy without rescuing OXPHOS impairment.\",\n      \"method\": \"Knock-in mouse models, proteomic profiling (soluble/insoluble fractions), cytochrome c rescue of respiration, OMA1 catalytic mutant cross, DELE1 cleavage assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cytochrome c biochemical rescue identifies specific mechanism, OMA1 epistasis dissects pathway, multiple orthogonal methods\",\n      \"pmids\": [\"41420107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHCHD10 deficiency in adipocytes disrupts mitochondrial cristae and OXPHOS complex assembly, impairing ATP generation; decreased ATP reduces lipolysis by lowering nascent ATGL protein synthesis, thereby suppressing UCP1-dependent thermogenesis; ATGL overexpression rescues thermogenesis in CHCHD10-knockout adipocytes.\",\n      \"method\": \"Adipocyte-specific CHCHD10 knockout mice, UCP1/ATP measurement, lipolysis assay, ATGL overexpression rescue, Seahorse bioenergetics\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined mechanistic rescue (ATGL overexpression), multiple orthogonal readouts\",\n      \"pmids\": [\"35709007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHCHD2 T61I mutation causes increased interaction between CHCHD2 and CHCHD10, leading to reduced CHCHD10 levels; mitochondrial ultrastructural alterations in CHCHD2 T61I patient fibroblasts resemble those of CHCHD10 mutation cells.\",\n      \"method\": \"Co-immunoprecipitation, CHCHD10 protein level measurement, patient fibroblast electron microscopy\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with protein level measurement, single lab\",\n      \"pmids\": [\"30530185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The N-terminal disordered domain of CHCHD10 forms amyloid fibrils whose cryo-EM structure shows that disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining their co-aggregation.\",\n      \"method\": \"CryoEM structure determination, amyloid fibril formation assay, mutant accommodation modeling\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure, but preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHCHD2 and CHCHD10 exist in mouse tissues as a high molecular weight complex whose levels increase in response to mitochondrial dysfunction; loss of CHCHD2 enhances cellular vulnerability to mitochondrial stress; CHCHD2 is required for normal striatal dopamine levels and lipid homeostasis in mouse brain.\",\n      \"method\": \"Chchd2 knockout mouse, BN-PAGE complex analysis, mitochondrial stress treatments, dopamine measurement, lipidomics\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with BN-PAGE complex identification, single lab\",\n      \"pmids\": [\"41053020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of chchd10 (but not chchd2) in zebrafish impairs assembly of mitochondrial respiratory Complex I; in double chchd10/chchd2 knockout zebrafish, Complex I impairment is unexpectedly restored via mtISR transcriptional activation, showing that the mt-ISR can compensate for Complex I deficiency.\",\n      \"method\": \"Zebrafish knockout models (single and double), Complex I assembly BN-PAGE, mt-ISR transcriptional markers, motor behavior assay\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vertebrate model, BN-PAGE complex assembly assay, single lab\",\n      \"pmids\": [\"36799027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHCHD10 deficiency in adipose tissue enhances adipogenesis and GSTA4 expression by activating a TDP43/Raptor/p62/Keap1/NRF2 axis; in hypertrophic adipocytes where p62 is reduced, this beneficial effect is eliminated.\",\n      \"method\": \"AT-specific Chchd10 KO mice, co-IP/pathway analysis, p62 manipulation, NRF2 reporter assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with pathway identification, single lab\",\n      \"pmids\": [\"39985288\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHCHD10 is a mitochondrial intermembrane space protein that, as part of the MICOS complex (with mitofilin/CHCHD3/CHCHD6), maintains cristae junction integrity and mitochondrial DNA stability; it forms heterodimers with its paralog CHCHD2 and interacts with Complex IV/COX, the prohibitin complex, SLP2, OMA1, PARL, and p32/C1QBP to regulate OXPHOS, cristae morphology, mtISR, mitophagy flux (via the PARL-PINK1 axis), and TDP-43 nuclear retention, with pathogenic mutations acting primarily through a toxic gain-of-function mechanism—protein misfolding/aggregation that disrupts IMS proteostasis, triggers aberrant OMA1-DELE1-HRI signaling, and impairs cytochrome c biogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CHCHD10 is a mitochondrial intermembrane space protein that maintains cristae architecture, oxidative phosphorylation, and mitochondrial DNA stability by functioning within the MICOS complex and as a heterodimer with its paralog CHCHD2. It interacts with cytochrome c oxidase (Complex IV) to scaffold COX activity, suppresses OMA1 protease activity to preserve long-form OPA1 and cristae junctions, and interacts with PARL to sustain PINK1-dependent mitophagy flux; during mitochondrial stress, CHCHD10 translocates to the cytosol to attenuate integrated stress response signaling by suppressing eIF2α phosphorylation [PMID:26666268, PMID:35173147, PMID:29540477, PMID:38132101]. Disease-associated mutations (e.g., S59L, R15L, G58R) act primarily through toxic gain-of-function aggregation that disrupts IMS proteostasis, activates the OMA1–DELE1–HRI stress axis, impairs cytochrome c biogenesis, and promotes cytoplasmic TDP-43 mislocalization, whereas complete loss of CHCHD10 alone does not recapitulate disease but impairs Complex I assembly and ATP-dependent processes including neuromuscular junction maintenance and adipocyte thermogenesis [PMID:30877432, PMID:35700042, PMID:41420107, PMID:31261376, PMID:35709007]. Mutations in CHCHD10 cause frontotemporal dementia–amyotrophic lateral sclerosis spectrum disease and motor neuron disease [PMID:24934289, PMID:29315381].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that CHCHD10 participates in oxidative phosphorylation answered the basic question of what this uncharacterized CHCH-domain protein does: it is required for Complex IV activity.\",\n      \"evidence\": \"siRNA knockdown with Complex IV activity assay in vitro\",\n      \"pmids\": [\"20888800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single complex assayed\", \"No mechanism for how CHCHD10 supports Complex IV identified\", \"Broader OXPHOS roles not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Localization of CHCHD10 to the intermembrane space at cristae junctions and demonstration that the S59L mutation disrupts cristae established the protein as a structural organizer of mitochondrial inner membrane architecture and linked it to FTD-ALS.\",\n      \"evidence\": \"Immunofluorescence, subcellular fractionation, and electron microscopy of S59L-overexpressing HeLa cells; genetic linkage in FTD-ALS family\",\n      \"pmids\": [\"24934289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous complex membership not yet identified\", \"Whether loss-of-function or gain-of-function drives disease was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of CHCHD10 as a component of the MICOS complex (with mitofilin, CHCHD3, CHCHD6) explained how it organizes cristae junctions and revealed that disease mutations cause MICOS disassembly, nucleoid loss, and impaired mtDNA repair.\",\n      \"evidence\": \"Co-immunoprecipitation in patient fibroblasts, electron microscopy, nucleoid staining, cytochrome c release assay\",\n      \"pmids\": [\"26666268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural contacts within MICOS not resolved\", \"Whether CHCHD10 is a core or peripheral MICOS subunit unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that CHCHD10 promotes nuclear retention of TDP-43 and that disease mutations cause cytoplasmic TDP-43 mislocalization connected mitochondrial dysfunction to a hallmark of ALS/FTD pathology.\",\n      \"evidence\": \"C. elegans genetic complementation, mammalian cell overexpression, primary neuron and mouse brain TDP-43 localization\",\n      \"pmids\": [\"28585542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CHCHD10 retains TDP-43 in the nucleus not identified\", \"Whether TDP-43 mislocalization is a cause or consequence of mitochondrial damage unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Multiple studies converged to define CHCHD10's molecular partnerships and biogenesis: it forms heterodimers with CHCHD2 in a stress-responsive ~220 kDa complex, interacts with p32/C1QBP, scaffolds COX activity via CHCHD2/ABL2, and requires Mia40-dependent disulfide bond formation for mitochondrial import; disease mutations disrupt these interactions through distinct mechanisms (import failure, destabilization, or aberrant binding).\",\n      \"evidence\": \"Co-IP/MS interactome, BN-PAGE, COX co-purification and activity assay, Mia40 knockdown/rescue, truncation mutagenesis, zebrafish knockdown, patient fibroblasts, multiple disease mutants tested across labs\",\n      \"pmids\": [\"29112723\", \"29121267\", \"29540477\", \"30084972\", \"29789341\", \"29315381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the ~220 kDa complex not determined\", \"Whether nuclear CHCHD10-CXXC5 interaction is physiologically significant in vivo unclear\", \"Structural basis of heterodimer formation unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Comparison of S55L knock-in versus CHCHD10-knockout mice resolved the disease mechanism debate: mutant protein aggregates activate mtISR via mTORC1 in a toxic gain-of-function manner, while knockout alone does not cause neurodegeneration; separately, muscle-conditional knockout revealed that CHCHD10 maintains neuromuscular junction integrity through ATP-dependent AChR clustering.\",\n      \"evidence\": \"Knock-in vs. knockout mouse comparison, aggregation analysis, transcriptomics/metabolomics, muscle-conditional KO with electrophysiology and ATP rescue\",\n      \"pmids\": [\"30877432\", \"31261376\", \"30874923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why aggregate toxicity is tissue-selective not explained\", \"Whether gain-of-function and haploinsufficiency mechanisms coexist for different mutations not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of OMA1-mediated L-OPA1 cleavage as the effector of cristae disruption in CHCHD2/CHCHD10 double-knockout mice provided the first enzymatic mechanism linking CHCHD10 loss to mitochondrial fragmentation, and revealed that TDP-43 overexpression itself reduces CHCHD10 levels to disrupt OPA1-mitofilin complexes.\",\n      \"evidence\": \"CHCHD2/CHCHD10 double-KO mice, OMA1 activation and OPA1 cleavage assays, Co-IP in FTLD-TDP patient brain, CHCHD10 overexpression rescue\",\n      \"pmids\": [\"32338760\", \"32369233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHCHD10 inhibits OMA1 at the molecular level unknown\", \"Whether OPA1-mitofilin disruption is the primary driver or one of several parallel cascades uncertain\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multi-omics of R15L patient fibroblasts revealed that Complex I deficiency drives a metabolic cascade (elevated NADH/NAD+, AMPK activation, mTORC1 inhibition, UPR activation), while Drosophila/cell studies showed that S59L activates TDP-43 and PINK1 pathways independently, with pharmacological PINK1 modulation providing rescue.\",\n      \"evidence\": \"Integrated transcriptomics/metabolomics/proteomics in patient fibroblasts, Drosophila transgenic model with PINK1 genetic/pharmacological epistasis, TDP-43 mitochondrial import inhibitor peptide\",\n      \"pmids\": [\"33749723\", \"33772006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PINK1 pathway activation is protective or pathogenic across all mutation types not established\", \"Therapeutic potential of TDP-43 import inhibition not tested in mammalian models\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The OMA1–DELE1–HRI signaling axis was identified as both a pathogenic output and a protective response in CHCHD10 disease: CHCHD10/CHCHD2 normally suppress OMA1 and cytosolic eIF2α phosphorylation, while OMA1-dependent DELE1 cleavage is required for survival of G58R knock-in mice; simultaneously, S59L aggregates destabilize the SLP2-prohibitin complex upstream of OMA1, and WT CHCHD10 directly inhibits TDP-43 aggregation in reconstituted systems.\",\n      \"evidence\": \"Co-IP with OMA1 and SLP2/PHB, OMA1 KO genetic cross in KI mice, DELE1 cleavage assay, eIF2α phosphorylation, cell-free TDP-43 aggregation with atomic force microscopy\",\n      \"pmids\": [\"35173147\", \"35700042\", \"35656794\", \"35787294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OMA1 suppression and mtISR attenuation are independent or sequential functions of CHCHD10 not resolved\", \"Direct binding interface between CHCHD10 and OMA1 not structurally defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that CHCHD10 interacts with PARL to suppress its protease activity, thereby sustaining PINK1 for mitophagy, provided the mechanistic link between CHCHD10 mutations and impaired mitophagy flux that promotes TDP-43 aggregation.\",\n      \"evidence\": \"Co-IP with PARL, PINK1 level measurement, mitophagy flux and Parkin recruitment assays in mouse and human FTD brain\",\n      \"pmids\": [\"38132101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PARL interaction is direct or mediated through the PHB/SLP2 platform not determined\", \"Relative contribution of impaired mitophagy vs. direct aggregation to TDP-43 pathology unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The pathogenic cascade was further refined: mutant CHCHD10 disrupts IMS copper homeostasis and cytochrome c biogenesis, and exogenous cytochrome c rescues respiration, pinpointing IMS proteostasis failure as a proximal cause; OMA1 catalytic blunting delays cardiomyopathy but does not rescue OXPHOS, separating the stress-signaling and bioenergetic arms of disease.\",\n      \"evidence\": \"Knock-in mouse proteomic profiling, cytochrome c biochemical rescue of respiration, OMA1 E324Q catalytic mutant cross\",\n      \"pmids\": [\"41420107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mutant CHCHD10 specifically impairs copper delivery or cytochrome c maturation not resolved\", \"Whether IMS proteostasis disruption is reversible therapeutically not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of the CHCHD10-CHCHD2 heterodimer and its interfaces with OMA1, PARL, and MICOS components; the basis for tissue-selective vulnerability in gain-of-function disease; and whether therapeutic strategies targeting OMA1, PINK1, or TDP-43 mitochondrial import can modify disease course in mammalian models.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the CHCHD10-CHCHD2 complex or its interaction interfaces\", \"Tissue-selective vulnerability mechanism unexplained\", \"No preclinical therapeutic efficacy data in mammalian ALS/FTD models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 19]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 4, 7, 15, 22, 23]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 10, 11, 15, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 9, 12]}\n    ],\n    \"complexes\": [\n      \"MICOS complex\",\n      \"CHCHD10-CHCHD2 heterodimer\",\n      \"SLP2-prohibitin complex\"\n    ],\n    \"partners\": [\n      \"CHCHD2\",\n      \"IMMT\",\n      \"CHCHD3\",\n      \"CHCHD6\",\n      \"C1QBP\",\n      \"SLP2\",\n      \"OMA1\",\n      \"PARL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}