{"doi":"10.1126/sciadv.adu0726","title":"CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology","abstract":"Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil–helix–coiled-coil–helix domain–containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein. In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.","journal":"Science Advances","year":2025,"id":527517,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1327516,"name":"Kohei Kano","orcid":"0000-0002-0223-5781","position":1,"is_corresponding":false},{"id":266477,"name":"Sadhna Phanse","orcid":"0000-0001-6306-0551","position":2,"is_corresponding":false},{"id":468136,"name":"Mai K. Nguyen","orcid":"0000-0003-3550-7728","position":3,"is_corresponding":false},{"id":589306,"name":"Elyssa B. Margolis","orcid":"0000-0001-8777-302X","position":4,"is_corresponding":false},{"id":668237,"name":"YuHong Fu","orcid":"0000-0003-4539-2039","position":5,"is_corresponding":false},{"id":1117959,"name":"Jonathan X. Meng","orcid":"0000-0002-4315-3483","position":6,"is_corresponding":false},{"id":291783,"name":"Mohamed Taha Moutaoufik","orcid":"0000-0002-2013-1601","position":7,"is_corresponding":false},{"id":291665,"name":"Zac Chatterton","orcid":"0000-0002-6683-1400","position":8,"is_corresponding":false},{"id":297865,"name":"Tatiana D. Saccon","orcid":"0000-0001-5328-4922","position":9,"is_corresponding":false},{"id":340741,"name":"Kirsten Broderick","orcid":null,"position":10,"is_corresponding":false},{"id":1329747,"name":"H Aoki","orcid":"0009-0005-9143-086X","position":11,"is_corresponding":false},{"id":290082,"name":"Jeffrey A. Simms","orcid":null,"position":12,"is_corresponding":false},{"id":1404833,"name":"Felicia Suteja","orcid":null,"position":13,"is_corresponding":false},{"id":230097,"name":"Yoshitaka Sei","orcid":"0000-0002-4725-8725","position":14,"is_corresponding":false},{"id":226820,"name":"Eric J. Huang","orcid":"0000-0002-5381-3801","position":15,"is_corresponding":false},{"id":348836,"name":"Kevin McAvoy","orcid":"0000-0002-0025-1921","position":16,"is_corresponding":false},{"id":368949,"name":"Giovanni Manfredi","orcid":"0000-0003-3893-1348","position":17,"is_corresponding":false},{"id":291678,"name":"Glenda M. Halliday","orcid":"0000-0003-0422-8398","position":18,"is_corresponding":false},{"id":291793,"name":"Mohan Babu","orcid":"0000-0003-4118-6406","position":19,"is_corresponding":false},{"id":468139,"name":"Ken Nakamura","orcid":"0000-0002-9192-182X","position":20,"is_corresponding":false},{"id":733436,"name":"Szu-Chi Liao","orcid":"0000-0003-2744-363X","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41237231","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}