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The transfer of Ca<jats:sup>2+<\/jats:sup> from the SR via RyR2 to mitochondria is thought to play a key role in matching increased metabolic demand during stress. In this study, we investigated whether augmented RyR2 activity results in self-imposed exacerbation of SR Ca<jats:sup>2+<\/jats:sup> leak, via altered SR-mitochondrial Ca<jats:sup>2+<\/jats:sup> transfer and elevated mito-ROS emission. Fluorescent indicators and spatially restricted genetic ROS probes revealed that both pharmacologically and genetically enhanced RyR2 activity, in ventricular myocytes from rats and catecholaminergic polymorphic ventricular tachycardia (CPVT) mice, respectively, resulted in increased ROS emission under \u03b2-adrenergic stimulation. Expression of mitochondrial Ca<jats:sup>2+<\/jats:sup> probe mtRCamp1h revealed diminished net mitochondrial [Ca<jats:sup>2+<\/jats:sup>] with enhanced SR Ca<jats:sup>2+<\/jats:sup> leak, accompanied by depolarization of the mitochondrial matrix. While this may serve as a protective mechanism to prevent mitochondrial Ca<jats:sup>2+<\/jats:sup> overload, protection is not complete and enhanced mito-ROS emission resulted in oxidation of RyR2, further amplifying proarrhythmic SR Ca<jats:sup>2+<\/jats:sup> release. Importantly, the effects of augmented RyR2 activity could be attenuated by mitochondrial ROS scavenging, and experiments with dominant-negative paralogs of the mitochondrial Ca<jats:sup>2+<\/jats:sup> uniporter (MCU) supported the hypothesis that SR-mitochondria Ca<jats:sup>2+<\/jats:sup> transfer is essential for the increase in mito-ROS. We conclude that in a process whereby leak begets leak, augmented RyR2 activity modulates mitochondrial Ca<jats:sup>2+<\/jats:sup> handling, promoting mito-ROS emission and driving further channel activity in a proarrhythmic feedback cycle in the diseased heart.<\/jats:p>","DOI":"10.1007\/s00395-020-0797-z","type":"journal-article","created":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T11:03:34Z","timestamp":1594119814000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":122,"title":["Increased RyR2 activity is exacerbated by calcium leak-induced mitochondrial ROS"],"prefix":"10.1007","volume":"115","author":[{"given":"Shanna","family":"Hamilton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radmila","family":"Terentyeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fruzsina","family":"Perger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaoni","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Stepanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.","family":"Bonilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn C.","family":"Knollmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemyslaw B.","family":"Radwa\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandor","family":"Gy\u00f6rke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy E.","family":"Belevych","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-7384","authenticated-orcid":false,"given":"Dmitry","family":"Terentyev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,22]]},"reference":[{"key":"797_CR1","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3389\/fnmol.2013.00002","volume":"4","author":"J Akerboom","year":"2013","unstructured":"Akerboom J, Carreras Calder\u00f3n N, Tian L, Wabnig S, Prigge M, Tol\u00f6 J, Gordus A, Orger MB, Severi KE, Macklin JJ, Patel R, Pulver SR, Wardill TJ, Fischer E, Sch\u00fcler C, Chen TW, Sarkisyan KS, Marvin JS, Bargmann CI, Kim DS, K\u00fcgler S, Lagnado L, Hegemann P, Gottschalk A, Schreiter ER, Looger LL (2013) Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics. 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