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to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH<jats:sub>2<\/jats:sub>) required for ATP production and reactive oxygen species (ROS) elimination.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase II (CaMKII) has been proposed to regulate mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake via mitochondrial Ca<jats:sup>2+<\/jats:sup> uniporter phosphorylation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We used two mouse models with either global deletion of CaMKII\u03b4 (CaMKII\u03b4 knockout) or cardiomyocyte\u2010specific deletion of CaMKII\u03b4 and \u03b3 (CaMKII\u03b4\/\u03b3 double knockout) to interrogate whether CaMKII controls mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake in isolated mitochondria and during \u03b2\u2010adrenergic stimulation in cardiac myocytes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>CaMKII\u03b4\/\u03b3 did not control Ca<jats:sup>2+<\/jats:sup> uptake, respiration or ROS emission in isolated cardiac mitochondria, nor in isolated cardiac myocytes, during \u03b2\u2010adrenergic stimulation and pacing.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The results of the present study do not support a relevant role of CaMKII for mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake in cardiac myocytes under physiological conditions.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Mitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca<jats:sup>2+<\/jats:sup>, which is taken up into mitochondria via the mitochondrial Ca<jats:sup>2+<\/jats:sup> uniporter (MCU). It was recently proposed that Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase II (CaMKII) regulates Ca<jats:sup>2+<\/jats:sup> uptake by interacting with the MCU, thereby affecting mPTP activation and programmed cell death. In the present study, we investigated the role of CaMKII under physiological conditions in which mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake matches energy supply to the demand of cardiac myocytes. Accordingly, we measured mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake in isolated mitochondria and cardiac myocytes harvested from cardiomyocyte\u2010specific CaMKII \u03b4 and \u03b3 double knockout (KO) (CaMKII\u03b4\/\u03b3 DKO) and global CaMKII\u03b4 KO mice. To simulate a physiological workload increase, cardiac myocytes were subjected to \u03b2\u2010adrenergic stimulation (by isoproterenol superfusion) and an increase in stimulation frequency (from 0.5 to 5\u00a0Hz). No differences in mitochondrial Ca<jats:sup>2+<\/jats:sup> accumulation were detected in isolated mitochondria or cardiac myocytes from both CaMKII KO models compared to wild\u2010type littermates. Mitochondrial redox state and ROS production were unchanged in CaMKII\u03b4\/\u03b3 DKO, whereas we observed a mild oxidation of mitochondrial redox state and an increase in H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> emission from CaMKII\u03b4 KO cardiac myocytes exposed to an increase in workload. In conclusion, the results obtained in the present study do not support the regulation of mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake via the MCU or mPTP activation by CaMKII in cardiac myocytes under physiological conditions.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276766","type":"journal-article","created":{"date-parts":[[2019,2,16]],"date-time":"2019-02-16T09:24:42Z","timestamp":1550309082000},"page":"1361-1376","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["CaMKII does not control mitochondrial Ca<sup>2+<\/sup> uptake in cardiac myocytes"],"prefix":"10.1113","volume":"598","author":[{"given":"Alexander G.","family":"Nickel","sequence":"first","affiliation":[{"name":"Comprehensive Heart Failure Center (CHFC) University Clinic W\u00fcrzburg  W\u00fcrzburg Germany"},{"name":"Affiliation when\/at which experiments were performed: Clinic III for Internal Medicine University Clinic Homburg  Homburg Germany"}]},{"given":"Michael","family":"Kohlhaas","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center (CHFC) University Clinic W\u00fcrzburg  W\u00fcrzburg Germany"},{"name":"Affiliation when\/at which experiments were performed: Clinic III for Internal Medicine University Clinic Homburg  Homburg Germany"}]},{"given":"Edoardo","family":"Bertero","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center (CHFC) University Clinic W\u00fcrzburg  W\u00fcrzburg Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0386-6702","authenticated-orcid":false,"given":"Daniel","family":"Wilhelm","sequence":"additional","affiliation":[{"name":"Affiliation when\/at which experiments were performed: Clinic III for Internal Medicine University Clinic Homburg  Homburg Germany"}]},{"given":"Michael","family":"Wagner","sequence":"additional","affiliation":[{"name":"Affiliation when\/at which experiments were performed: Clinic III for Internal Medicine University Clinic Homburg  Homburg Germany"},{"name":"Institute for Molecular Cell Biology Saarland University  Homburg Germany"}]},{"given":"Vasco","family":"Sequeira","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center (CHFC) University Clinic W\u00fcrzburg  W\u00fcrzburg Germany"}]},{"given":"Michael M.","family":"Kreusser","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiology Heidelberg University Hospital  Heidelberg Germany"},{"name":"German Center for Cardiovascular Research (DZHK) partner site Heidelberg\/Mannheim  Germany"},{"name":"Department of Cardiology Heidelberg University Hospital  Heidelberg Germany"}]},{"given":"Matthias","family":"Dewenter","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiology Heidelberg University Hospital  Heidelberg Germany"},{"name":"German Center for Cardiovascular Research (DZHK) partner site Heidelberg\/Mannheim  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