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This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies also demonstrate that preconditioning with this compound preserves the ATP levels during cardiac ischemia in rats. The molecular mechanisms by which FTY720 promotes metabolism are not well understood. Here, we demonstrate that nanomolar concentrations of the phosphorylated form of FTY720 (FTY720-P), the active ligand of S1P receptor (S1PR), activates mitochondrial respiration and the mitochondrial ATP production rate in AC16 human cardiomyocyte cells. Additionally, FTY720-P increases the number of mitochondrial nucleoids, promotes mitochondrial morphology alterations, and induces activation of STAT3, a transcription factor that promotes mitochondrial function. Notably, the effect of FTY720-P on mitochondrial function was suppressed in the presence of a STAT3 inhibitor. In summary, our results suggest that FTY720 promotes the activation of mitochondrial function, in part, through a STAT3 action.<\/jats:p>","DOI":"10.3390\/ijms24087374","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T04:45:32Z","timestamp":1681706732000},"page":"7374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0912-4168","authenticated-orcid":false,"given":"Juan Pablo","family":"Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"S\u00e0nchez-Fern\u00e0ndez-de-Landa","sequence":"additional","affiliation":[{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), 28029 Madrid, Spain"},{"name":"Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain"},{"name":"Departament de Bioqu\u00edmica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena Mar\u00eda Goretti","family":"Diarte-A\u00f1azco","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Zorzano","sequence":"additional","affiliation":[{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), 28029 Madrid, Spain"},{"name":"Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain"},{"name":"Departament de Bioqu\u00edmica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7380-5385","authenticated-orcid":false,"given":"Francisco","family":"Blanco-Vaca","sequence":"additional","affiliation":[{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), 28029 Madrid, Spain"},{"name":"Department of Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Department de Bioqu\u00edmica i Biologia Molecular, Universitat Aut\u00f2noma de Barcelona, 08041 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6531-2246","authenticated-orcid":false,"given":"Josep","family":"Julve","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), 28029 Madrid, Spain"},{"name":"Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1056\/NEJMoa052643","article-title":"Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis","volume":"355","author":"Kappos","year":"2006","journal-title":"N. 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