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PPCI is effective at reperfusing the heart; however, the rapid reintroduction of blood can cause ischemia-reperfusion (I\/R). Reperfusion injury is responsible for up to half of the total myocardial damage, but there are no pharmacological interventions to reduce I\/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and redirecting pyruvate toward oxidation can blunt hypertrophy. We hypothesized that this pathway might be important during I\/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. After I\/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I\/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (\u0394\u03a8), and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , increased pyruvate entry to the TCA cycle, increased oxygen consumption, and improved myocardial salvage and functional outcomes following I\/R. Our data suggest normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I\/R injury.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.180906","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T12:09:05Z","timestamp":1721909345000},"source":"Crossref","is-referenced-by-count":30,"title":["Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart"],"prefix":"10.1172","volume":"9","author":[{"given":"Joseph R.","family":"Visker","sequence":"first","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7612-8375","authenticated-orcid":true,"given":"Ahmad A.","family":"Cluntun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, University of Utah, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse N.","family":"Velasco-Silva","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, University of Utah, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Eberhardt","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Cede\u00f1o-Rosario","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, University of Utah, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thirupura S.","family":"Shankar","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Hamouche","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ling","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoin","family":"Kwak","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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