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Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of <jats:italic>Mic60<\/jats:italic> reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age\u2010dependent manner. Moreover, haploinsufficiency of <jats:italic>Mic60<\/jats:italic> compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N\u2010acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo\u2010insufficient <jats:italic>Mic60<\/jats:italic> mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies.<\/jats:p>","DOI":"10.1111\/bpa.13157","type":"journal-article","created":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T08:39:45Z","timestamp":1679992785000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy"],"prefix":"10.1111","volume":"33","author":[{"given":"Tingting","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College, Neuroscience Center Chinese Academy of Medical Sciences  Beijing 100005 China"},{"name":"Biobank of Ninth People's Hospital Shanghai Jiao Tong University School of 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