{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T23:13:54Z","timestamp":1768259634226,"version":"3.49.0"},"reference-count":59,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,3]],"date-time":"2021-01-03T00:00:00Z","timestamp":1609632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence\/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin\/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.<\/jats:p>","DOI":"10.3390\/ijms22010424","type":"journal-article","created":{"date-parts":[[2021,1,3]],"date-time":"2021-01-03T19:54:46Z","timestamp":1609703686000},"page":"424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity"],"prefix":"10.3390","volume":"22","author":[{"given":"Vlad F.","family":"Avram","sequence":"first","affiliation":[{"name":"Department of Internal Medicine-Diabetes, Nutrition and Metabolic Diseases, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy Timi\u0219oara, Romania, Eftimie Murgu Sq. No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Center for Translational Research and Systems Medicine, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy Timi\u0219oara, Romania, Spl. Tudor Vladimirescu No. 14, 300173 Timi\u0219oara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6919-585X","authenticated-orcid":false,"given":"Imen","family":"Chamkha","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden"},{"name":"Abliva AB, Medicon Village, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8426-4836","authenticated-orcid":false,"given":"Eleonor","family":"\u00c5sander-Frostner","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden"},{"name":"Abliva AB, Medicon Village, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2417-5767","authenticated-orcid":false,"given":"Johannes K.","family":"Ehinger","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden"},{"name":"Abliva AB, Medicon Village, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romulus Z.","family":"Timar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Diabetes, Nutrition and Metabolic Diseases, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy Timi\u0219oara, Romania, Eftimie Murgu Sq. No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Center for Translational Research and Systems Medicine, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy Timi\u0219oara, Romania, Spl. Tudor Vladimirescu No. 14, 300173 Timi\u0219oara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magnus J.","family":"Hansson","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden"},{"name":"Abliva AB, Medicon Village, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danina M.","family":"Muntean","sequence":"additional","affiliation":[{"name":"Center for Translational Research and Systems Medicine, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy Timi\u0219oara, Romania, Spl. Tudor Vladimirescu No. 14, 300173 Timi\u0219oara, Romania"},{"name":"Department of Functional Sciences-Pathophysiology, 2Center for Translational Research and Systems Medi-cine, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy Timi\u0219oara, Romania, Eftimie Murgu Sq. No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7901-1826","authenticated-orcid":false,"given":"Eskil","family":"Elm\u00e9r","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden"},{"name":"Abliva AB, Medicon Village, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart Disease and Stroke Statistics\u20142019 Update: A Report From the American Heart Association","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"ref_2","unstructured":"Mach, F., Baigent, C., Catapano, A.L., Koskinas, K.C., Casula, M., Badimon, L., Chapman, M.J., De Backer, G.G., Delgado, V., and Ference, B.A. (2019). 2019 ESC\/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). 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