{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T09:49:41Z","timestamp":1792748981709,"version":"4.5.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,6,21]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Calcium (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ) uptake by mitochondria occurs via the mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uniporter. Mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>m<\/jats:sub>\n                      ) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      MICU3 knock out hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>m<\/jats:sub>\n                      than wild-type hearts following acute isoproterenol infusion. In contrast, heart with overexpression of MICU3 exhibited an enhanced increase in [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>m<\/jats:sub>\n                      compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, mice with overexpression of MICU3 exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in hearts with overexpression of MICU3 compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>m<\/jats:sub>\n                      in the heart. We conclude that MICU3 plays an important role in regulating [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>m<\/jats:sub>\n                      physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.123.324026","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T05:00:30Z","timestamp":1715749230000},"page":"26-40","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy"],"prefix":"10.1161","volume":"135","author":[{"given":"Barbara","family":"Roman","sequence":"first","affiliation":[{"name":"Cardiac Physiology Lab (B.R., Y.M., J.S., E.M., G.H.), National Heart, Lung, and Blood Institute, National 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Minneapolis, MN (H.C.V., J.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Hinojosa","sequence":"additional","affiliation":[{"name":"Cardiac Physiology Lab (B.R., Y.M., J.S., E.M., G.H.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-9744","authenticated-orcid":true,"given":"Danielle","family":"Springer","sequence":"additional","affiliation":[{"name":"Mouse Phenotyping Core (D.S.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8604-1633","authenticated-orcid":true,"given":"Julia C.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN (H.C.V., 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