{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:56:13Z","timestamp":1788897373635,"version":"build-2803163510"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Metabolic disturbances are key contributors to myocardial ischemia-reperfusion (I\/R) injury, yet the underlying molecular mechanisms remain largely unclear. Rho family GTPase 3 (RND3), a cytosolic small guanosine triphosphatase (GTPase) known to antagonize ROCK1 (Rho-associated coiled-coil kinase 1), has been implicated in several cardiovascular disorders. However, its mitochondrial localization and functional role in cardiac energy metabolism and I\/R injury remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      A murine model of myocardial I\/R injury was established through left anterior descending coronary artery ligation. Mice with cardiomyocyte-specific knockout and overexpression of\n                      <jats:italic toggle=\"yes\">Rnd3<\/jats:italic>\n                      were generated. To investigate the role of RND3 in cardiac metabolism and I\/R injury, we used\n                      <jats:sup>13<\/jats:sup>\n                      C-nuclear magnetic resonance,\n                      <jats:sup>18<\/jats:sup>\n                      F-fluorodeoxyglucose positron emission tomography\/computed tomography scanning, seahorse mitochondrial energy metabolism assays, and\n                      <jats:sup>13<\/jats:sup>\n                      C-metabolic flux tracing. Mechanistic studies were conducted using RNA sequencing, coimmunoprecipitation, mass spectrometry, and glutathione S-transferase (GST) pulldown assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Cardiomyocyte-specific deletion of\n                      <jats:italic toggle=\"yes\">Rnd3<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Rnd3<\/jats:italic>\n                      conditional knockout,\n                      <jats:italic toggle=\"yes\">Rnd3<\/jats:italic>\n                      <jats:sup>cKO<\/jats:sup>\n                      ) resulted in impaired glucose oxidation and compensatory upregulation of fatty acid oxidation, leading to pronounced cardiac dysfunction and increased mortality.\n                      <jats:italic toggle=\"yes\">Rnd3<\/jats:italic>\n                      <jats:sup>cKO<\/jats:sup>\n                      hearts exhibited reduced pyruvate\/malate-driven complex I respiration and marked uncoupling between glycolysis and the tricarboxylic acid cycle. Mechanistically, RND3 was identified as a novel mitochondrial matrix-localized small GTPase that directly binds to ACAT1 (acetyl-coenzyme A [CoA] acetyltransferase), disrupting its interaction with PDHA1 (pyruvate dehydrogenase E1\u03b1 subunit) and thereby promoting PDHA1 acetylation and glucose oxidation. It is important to note that RND3 expression was significantly downregulated in both human and murine hearts after I\/R insult. Loss of RND3 sensitized the hearts to I\/R injury, as evidenced by reduced levels of phosphocreatine and ATP. Conversely, cardiac-specific overexpression of\n                      <jats:italic toggle=\"yes\">Rnd3<\/jats:italic>\n                      conferred protection against I\/R injury, an effect that was abolished upon\n                      <jats:italic toggle=\"yes\">Pdha1<\/jats:italic>\n                      knockdown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our results identify RND3 as a novel mitochondria-localized regulator of glucose oxidation that safeguards the heart against I\/R injury. Therapeutic reconstitution of\n                      <jats:italic toggle=\"yes\">Rnd3<\/jats:italic>\n                      may represent a promising strategy to restore metabolic homeostasis and mitigate myocardial damage in the context of I\/R.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.075591","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T09:00:15Z","timestamp":1781168415000},"page":"37-57","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["RND3 Enhances Cardiac Glucose Metabolism Through Inhibiting ACAT1-Dependent PDHA1 Acetylation and Protects Against Ischemia-Reperfusion Injury"],"prefix":"10.1161","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6633-6147","authenticated-orcid":true,"given":"Zhenyu","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Cardiology, Sixth Medical Center, Chinese People\u2019s Liberation Army General Hospital, Beijing, China (Z.X., Y.L., J. Liu, Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8220-5530","authenticated-orcid":true,"given":"Yueyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Sixth Medical Center, Chinese People\u2019s Liberation Army General Hospital, Beijing, China (Z.X., Y.L., J. Liu, Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6314-4146","authenticated-orcid":true,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019 an, China (Y.Z., M.Q., H.Z., X.Z., M.J., C.L., J. Lin, D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5099-5934","authenticated-orcid":true,"given":"Zhengjun","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Diagnosis, No. 941 Hospital of Joint Logistics Support Force, Xining, China (Z.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9045-5135","authenticated-orcid":true,"given":"Meiying","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019 an, China (Y.Z., M.Q., H.Z., X.Z., M.J., C.L., J. Lin, D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5188-9324","authenticated-orcid":true,"given":"Huanle","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019 an, China (Y.Z., M.Q., H.Z., X.Z., M.J., C.L., J. Lin, D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1707-6346","authenticated-orcid":true,"given":"Xiaohua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019 an, China (Y.Z., M.Q., H.Z., X.Z., M.J., C.L., J. Lin, D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0508-9916","authenticated-orcid":true,"given":"Mengyuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019 an, China (Y.Z., M.Q., H.Z., X.Z., M.J., C.L., J. Lin, D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2015-1590","authenticated-orcid":true,"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Sixth Medical Center, Chinese People\u2019s Liberation Army General Hospital, Beijing, China (Z.X., Y.L., J. 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