{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:20:10Z","timestamp":1778170810199,"version":"3.51.4"},"reference-count":87,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jordan Family Foundation","award":["NIH R35GM131795"],"award-info":[{"award-number":["NIH R35GM131795"]}]},{"name":"Jordan Family Foundation","award":["NIH T32 DK007120"],"award-info":[{"award-number":["NIH T32 DK007120"]}]},{"name":"BJC Investigator Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy.<\/jats:p>","DOI":"10.3390\/ijms262210977","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:10:45Z","timestamp":1763025045000},"page":"10977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8461-7854","authenticated-orcid":false,"given":"Neil V.","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94704, USA"},{"name":"Department of Pediatrics, University of California, San Francisco, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Guerra","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7231-2161","authenticated-orcid":false,"given":"Justin Y.","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94704, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Pagliarini","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Department of Biochemistry and Molecular BioPhysics, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5678-759X","authenticated-orcid":false,"given":"Elizabeth","family":"Theusch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Francisco, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4172-6815","authenticated-orcid":false,"given":"Ronald M.","family":"Krauss","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94704, USA"},{"name":"Department of Pediatrics, University of California, San Francisco, CA 90048, USA"},{"name":"Department of Medicine, University of California, San Francisco, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e012924","DOI":"10.1161\/JAHA.119.012924","article-title":"Cholesterol and atherosclerotic cardiovascular disease: A lifelong problem","volume":"8","author":"Gidding","year":"2019","journal-title":"J. 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