{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T13:08:33Z","timestamp":1773666513086,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,27]],"date-time":"2022-02-27T00:00:00Z","timestamp":1645920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["20-15-00120"],"award-info":[{"award-number":["20-15-00120"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>S-15176 difumarate salt, a derivative of the anti-ischemic metabolic drug trimetazidine, has been intensively studied for its impact on cellular metabolism in animal models of ischemia-reperfusion injury of the liver, heart, spinal cord, and other organs. Despite evidence of some reduction in oxidative damage to cells, the results of therapy with S-15176 have been mostly disappointing, possibly because of the lack of data on its underlying mechanisms. Here, we aimed to investigate in more detail the role of complexes I-IV of the electron transport chain and membrane permeability transition in mitochondrial toxicity associated with S-15176. Using rat thymocyte and liver mitochondria, we demonstrated that: (1) acute exposure to S-15176 (10 to 50 \u03bcM) dose-dependently decreased the mitochondrial membrane potential; (2) S-15176 suppressed the ADP-stimulated (State 3) and uncoupled (State 3UDNP) respiration of mitochondria energized with succinate or malate\/glutamate, but not ascorbate\/TMPD, and increased the resting respiration (State 4) when using all the substrate combinations; (3) S-15176 directly inhibited the activity of the respiratory complex III; (4) low doses of S-15176 diminished the rate of H2O2 production by mitochondria; (5) at concentrations of above 30 \u03bcM, S-15176 reduced calcium retention capacity and contributed to mitochondrial membrane permeabilization. Taken together, these findings suggest that S-15176 at tissue concentrations reached in animals can impair mitochondrial function through suppression of the cytochrome bc1 complex and an increase in the nonspecific membrane permeability.<\/jats:p>","DOI":"10.3390\/biology11030380","type":"journal-article","created":{"date-parts":[[2022,2,27]],"date-time":"2022-02-27T20:46:17Z","timestamp":1645994777000},"page":"380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["S-15176 Difumarate Salt Can Impair Mitochondrial Function through Inhibition of the Respiratory Complex III and Permeabilization of the Inner Mitochondrial Membrane"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5707-6557","authenticated-orcid":false,"given":"Natalia V.","family":"Belosludtseva","sequence":"first","affiliation":[{"name":"Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Moscow Region, Russia"},{"name":"Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Mari El, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vlada S.","family":"Starinets","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Moscow Region, Russia"},{"name":"Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Mari El, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4258-9015","authenticated-orcid":false,"given":"Alena A.","family":"Semenova","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Mari El, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia D.","family":"Igoshkina","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Mari El, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7453-3390","authenticated-orcid":false,"given":"Mikhail V.","family":"Dubinin","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Moscow Region, Russia"},{"name":"Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Mari El, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5392-7035","authenticated-orcid":false,"given":"Konstantin N.","family":"Belosludtsev","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Moscow Region, Russia"},{"name":"Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Mari El, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.31083\/j.rcm2204149","article-title":"The efficacy of trimetazidine in non-ischemic heart failure patients: A meta-analysis of randomized controlled trials","volume":"22","author":"Zhao","year":"2021","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1177\/0003319718780551","article-title":"Trimetazidine in the Prevention of Tissue Ischemic Conditions","volume":"70","author":"Kallistratos","year":"2019","journal-title":"Angiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ijcard.2019.05.063","article-title":"Trimetazidine in cardiovascular medicine","volume":"293","author":"Marzilli","year":"2019","journal-title":"Int. J. 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