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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 \u03b1-synuclein. In idiopathic PD,\n                    <jats:italic toggle=\"yes\">CHCHD2<\/jats:italic>\n                    gene expression also correlated with \u03b1-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 \u03b1-synuclein aggregation and neurodegeneration.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adu0726","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T18:58:21Z","timestamp":1763146701000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2744-363X","authenticated-orcid":true,"given":"Szu-Chi","family":"Liao","sequence":"first","affiliation":[{"name":"Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA."},{"name":"Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA."},{"name":"Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0223-5781","authenticated-orcid":true,"given":"Kohei","family":"Kano","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6306-0551","authenticated-orcid":true,"given":"Sadhna","family":"Phanse","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Regina, Regina, Saskatchewan, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3550-7728","authenticated-orcid":true,"given":"Mai","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8777-302X","authenticated-orcid":true,"given":"Elyssa","family":"Margolis","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology, and Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA."},{"name":"Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-2039","authenticated-orcid":true,"given":"YuHong","family":"Fu","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA."},{"name":"Brain and Mind Centre and Faculty of Medicine and Health School of Medical Sciences, University of Sydney, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4315-3483","authenticated-orcid":true,"given":"Jonathan","family":"X. 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