{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:10:22Z","timestamp":1792671022672,"version":"4.5.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,11,19]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      The mitochondrial calcium uniporter (mtCU) is an \u2248700-kD multisubunit channel residing in the inner mitochondrial membrane required for mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      (\n                      <jats:sub>m<\/jats:sub>\n                      Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ) uptake. Here, we detail the contribution of MCUB, a paralog of the pore-forming subunit MCU, in mtCU regulation and function and for the first time investigate the relevance of MCUB to cardiac physiology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We created a stable\n                      <jats:italic>MCUB<\/jats:italic>\n                      knockout cell line (\n                      <jats:italic>MCUB<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) using CRISPR-Cas9n technology and generated a cardiac-specific, tamoxifen-inducible MCUB mutant mouse (CAG-CAT-MCUB x MCM; MCUB-Tg) for in vivo assessment of cardiac physiology and response to ischemia\/reperfusion injury. Live-cell imaging and high-resolution spectrofluorometery were used to determine intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      exchange and size-exclusion chromatography; blue native page and immunoprecipitation studies were used to determine the molecular function and impact of MCUB on the high-molecular-weight mtCU complex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Using genetic gain- and loss-of-function approaches, we show that MCUB expression displaces MCU from the functional mtCU complex and thereby decreases the association of mitochondrial calcium uptake 1 and 2 (MICU1\/2) to alter channel gating. These molecular changes decrease MICU1\/2\u2013dependent cooperative activation of the mtCU, thereby decreasing\n                      <jats:sub>m<\/jats:sub>\n                      Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uptake. Furthermore, we show that MCUB incorporation into the mtCU is a stress-responsive mechanism to limit\n                      <jats:sub>m<\/jats:sub>\n                      Ca\n                      <jats:sup>2+<\/jats:sup>\n                      overload during cardiac injury. Indeed, overexpression of MCUB is sufficient to decrease infarct size after ischemia\/reperfusion injury. However, MCUB incorporation into the mtCU does come at a cost; acute decreases in\n                      <jats:sub>m<\/jats:sub>\n                      Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uptake impair mitochondrial energetics and contractile function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      We detail a new regulatory mechanism to modulate mtCU function and\n                      <jats:sub>m<\/jats:sub>\n                      Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uptake. Our results suggest that MCUB-dependent changes in mtCU stoichiometry are a prominent regulatory mechanism to modulate\n                      <jats:sub>m<\/jats:sub>\n                      Ca\n                      <jats:sup>2+<\/jats:sup>\n                      uptake and cellular physiology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.118.037968","type":"journal-article","created":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T05:00:41Z","timestamp":1568869241000},"page":"1720-1733","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":150,"title":["MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Stress"],"prefix":"10.1161","volume":"140","author":[{"given":"Jonathan P.","family":"Lambert","sequence":"first","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy S.","family":"Luongo","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanendra","family":"Tomar","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Jadiya","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhe","family":"Gao","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Lucchese","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin W.","family":"Kolmetzky","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil S.","family":"Shah","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Elrod","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10234"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02246"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10230"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)50355-6"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.06.017"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.06.002"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22082"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2728(72)90161-2"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2868"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17656"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09358"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.02.032"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.04.020"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.10.011"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.07.011"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.11.064"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055785"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1242993"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.12.054"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.04.050"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.157"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.1.H429"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.478"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43171"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223925"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1208592"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1380.015"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/hh1301.092687"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11444"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1900107"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi2018909"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1280161"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1504705112"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00704"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.01.013"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.118.037968","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T03:53:26Z","timestamp":1715572406000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.118.037968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,19]]},"references-count":36,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2019,11,19]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.118.037968"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.118.037968","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,19]]},"assertion":[{"value":"2019-09-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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