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However, the underlying mechanisms are far from being understood. Using the colon ascendens stent peritonitis mouse model of sepsis (CASP), we examined the subcellular mechanisms that mediate sepsis\u2010induced apoptosis. Wild\u2010type (WT) CASP mice hearts showed an increase in apoptosis respect to WT\u2010Sham. CASP transgenic mice expressing a CaMKII inhibitory peptide (AC3\u2010I) were protected against sepsis\u2010induced apoptosis. Dantrolene, used to reduce ryanodine receptor (RyR) diastolic sarcoplasmic reticulum (SR) Ca<jats:sup>2+<\/jats:sup> release, prevented apoptosis in WT\u2010CASP. To examine whether CaMKII\u2010dependent RyR2 phosphorylation mediates diastolic Ca<jats:sup>2+<\/jats:sup> release and apoptosis in sepsis, we evaluated apoptosis in mutant mice hearts that have the CaMKII phosphorylation site of RyR2 (Serine 2814) mutated to Alanine (S2814A). S2814A CASP mice did not show increased apoptosis. Consistent with RyR2 phosphorylation\u2010dependent enhancement in diastolic SR Ca<jats:sup>2+<\/jats:sup> release leading to mitochondrial Ca<jats:sup>2+<\/jats:sup> overload, mitochondrial Ca<jats:sup>2+<\/jats:sup> retention capacity was reduced in mitochondria isolated from WT\u2010CASP compared to Sham and this reduction was absent in mitochondria from CASP S2814A or dantrolene\u2010treated mice. We conclude that in sepsis, CaMKII\u2010dependent RyR2 phosphorylation results in diastolic Ca<jats:sup>2+<\/jats:sup> release from SR which leads to mitochondrial Ca<jats:sup>2+<\/jats:sup> overload and apoptosis.<\/jats:p>","DOI":"10.1111\/jcmm.15470","type":"journal-article","created":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T08:41:19Z","timestamp":1595580079000},"page":"9627-9637","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["CaMKII\u2010dependent ryanodine receptor phosphorylation mediates sepsis\u2010induced cardiomyocyte apoptosis"],"prefix":"10.1111","volume":"24","author":[{"given":"Marisa","family":"Sep\u00falveda","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares Conicet La Plata Facultad de Ciencias M\u00e9dicas Universidad Nacional de La Plata La Plata Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan 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