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Pharmacologic inhibition of CPN1\/2 decreases cardiac injury during ischemia (ISC)\u2013reperfusion (REP) by improving mitochondrial function. However, the protein targets of CPN1\/2 activation during ISC\u2013REP are unclear. CPN1\/2 include a large subunit and a small regulatory subunit 1 (CPNS1). Genetic deletion of CPNS1 eliminates the activities of both CPN1 and CPN2. Conditional cardiomyocyte specific CPNS1 deletion mice were used in the present study to clarify the role of CPN1\/2 activation in mitochondrial damage during ISC\u2013REP with an emphasis on identifying the potential protein targets of CPN1\/2. Isolated hearts from wild type (WT) or CPNS1 deletion mice underwent 25\u00a0min in vitro global ISC and 30\u00a0min REP. Deletion of CPNS1 led to decreased cytosolic and mitochondrial calpain 1 activation compared to WT. Cardiac injury was decreased in CPNS1 deletion mice following ISC\u2013REP as shown by the decreased infarct size compared to WT. Compared to WT, mitochondrial function was improved in CPNS1 deletion mice following ischemia\u2013reperfusion as shown by the improved oxidative phosphorylation and decreased susceptibility to mitochondrial permeability transition pore opening. H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    generation was also decreased in mitochondria from deletion mice following ISC\u2013REP compared to WT. Deletion of CPNS1 also resulted in less cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    and truncated apoptosis inducing factor (tAIF) release from mitochondria. Proteomic analysis of the isolated mitochondria showed that deletion of CPNS1 increased the content of proteins functioning in regulation of mitochondrial calcium homeostasis (paraplegin and sarcalumenin) and complex III activity. These results suggest that activation of CPN1 increases cardiac injury during ischemia\u2013reperfusion by impairing mitochondrial function and triggering cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    and tAIF release from mitochondria into cytosol.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-03947-9","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T06:03:34Z","timestamp":1641535414000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Calpain-mediated protein targets in cardiac mitochondria following ischemia\u2013reperfusion"],"prefix":"10.1038","volume":"12","author":[{"given":"Ling","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J.","family":"Lesnefsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda","family":"Willard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"3947_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s00395-019-0726-1","volume":"114","author":"T Cao","year":"2019","unstructured":"Cao, T. et al. 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