{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:08:25Z","timestamp":1788520105495,"version":"build-2803163510"},"reference-count":64,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":193,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL-131673"],"award-info":[{"award-number":["R01 HL-131673"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p><jats:italic>Background<\/jats:italic>. Hypothermia (H), cardioplegia (CP), and both combined (HCP) are known to be protective against myocardial ischemia reperfusion (IR) injury. Mitochondria have molecular signaling mechanisms that are associated with both cell survival and cell death. In this study, we investigated the dynamic changes in proapoptotic and prosurvival signaling pathways mediating H, CP, or HCP\u2010induced protection of mitochondrial function after acute myocardial IR injury. <jats:italic>Methods<\/jats:italic>. Rats were divided into five groups. Each group consists of 3 subgroups based on a specific reperfusion time (5, 20, or 60\u2009min) after a 25\u2010min global ischemia. The time control (TC) groups were not subjected to IR but were perfused with 37 \u00b0C Krebs\u2010Ringer\u2019s (KR) buffer, containing 4.5\u2009mM\u2009K<jats:sup>+<\/jats:sup>, in a specific perfusion protocol that corresponded with the duration of each IR protocol. The IR group (control) was perfused for 20\u2009min with KR, followed by 25\u2010min global ischemia, and then KR reperfusion for 5, 20, or 60\u2009min. The treatment groups were exposed to 17 \u00b0C H, 37 \u00b0C CP (16\u2009mM\u2009K<jats:sup>+<\/jats:sup>), or HCP (17 \u00b0C\u2009+ CP) for 5\u2009min before ischemia and for 2\u2009min on reperfusion before switching to 37 \u00b0C KR perfusion for the remainder of each of the reperfusion times. Cardiac function and mitochondrial redox state (NADH\/FAD) were monitored online in the <jats:italic>ex vivo<\/jats:italic> hearts before, during, and after ischemia. Mitochondria were isolated at the end of each specified reperfusion time, and changes in O<jats:sub>2<\/jats:sub> consumption, membrane potential (<jats:italic>\u0394\u03a8<\/jats:italic><jats:sub>m<\/jats:sub>), and Ca<jats:sup>2+<\/jats:sup> retention capacity (CRC) were assessed using complex I and complex II substrates. In another set of hearts, mitochondrial and cytosolic fractions were isolated after a specified reperfusion time to conduct western blot assays to determine hexokinase II (HKII) and Bax binding\/translocation to mitochondria, cytosolic pAkt levels, and cytochrome <jats:italic>c<\/jats:italic> (Cyto\u2010<jats:italic>c<\/jats:italic>) release into the cytosol. <jats:italic>Results<\/jats:italic>. H and HCP were more protective of mitochondrial integrity and, concomitantly, cardiac function than CP alone; H and HCP improved post\u2010ischemic cardiac function by (1) maintaining mitochondrial bioenergetics, (2) maintaining HKII binding to mitochondria with an increase in pAkt levels, (3) increasing CRC, and (4) decreasing Cyto\u2010<jats:italic>c<\/jats:italic> release during reperfusion. Bax translocation\/binding to mitochondria was unaffected by any treatment, regardless of cardiac functional recovery. <jats:italic>Conclusions<\/jats:italic>. Hypothermia preserved mitochondrial function and cardiac function, in part, by maintaining mitochondrial bioenergetics, by retaining HKII binding to mitochondria via upstream pAkt, and by reducing Cyto\u2010<jats:italic>c<\/jats:italic> release independently of Bax binding to mitochondria.<\/jats:p>","DOI":"10.1155\/2022\/4476448","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T05:05:20Z","timestamp":1657775120000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hypothermia Prevents Cardiac Dysfunction during Acute Ischemia Reperfusion by Maintaining Mitochondrial Bioenergetics and by Promoting Hexokinase II Binding to Mitochondria"],"prefix":"10.1155","volume":"2022","author":[{"given":"Jie","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7798-4891","authenticated-orcid":false,"given":"Jyotsna","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David F.","family":"Stowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Heisner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Meng","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-1414","authenticated-orcid":false,"given":"Amadou K. 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