{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:50:23Z","timestamp":1790812223467,"version":"4.1.0"},"reference-count":58,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHR 1471\/1\u20101"],"award-info":[{"award-number":["SCHR 1471\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR 152"],"award-info":[{"award-number":["TRR 152"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001656","name":"Helmholtz-Gemeinschaft","doi-asserted-by":"publisher","award":["Initiative and Network Fund ExNet\u20100041\u2010Phase2\u20103"],"award-info":[{"award-number":["Initiative and Network Fund ExNet\u20100041\u2010Phase2\u20103"]}],"id":[{"id":"10.13039\/501100001656","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Treatment of cardiac arrhythmia remains challenging due to severe side effects of common anti\u2010arrhythmic drugs. We previously demonstrated that mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake in cardiomyocytes represents a promising new candidate structure for safer drug therapy. However, druggable agonists of mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake suitable for preclinical and clinical studies are still missing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Herewe screened 727 compounds with a history of use in human clinical trials in a three\u2010step screening approach. As a primary screening platform we used a permeabilized HeLa cell\u2010based mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake assay. Hits were validated in cultured HL\u20101 cardiomyocytes and finally tested for anti\u2010arrhythmic efficacy in three translational models: a Ca<jats:sup>2+<\/jats:sup> overload zebrafish model and cardiomyocytes of both a mouse model for catecholaminergic polymorphic ventricular tachycardia (CPVT) and induced pluripotent stem cell derived cardiomyocytes from a CPVT patient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We identifiedtwo candidate compounds, the clinically approved drugs ezetimibe and disulfiram, which stimulate SR\u2010mitochondria Ca<jats:sup>2+<\/jats:sup> transfer at nanomolar concentrations. This is significantly lower compared to the previously described mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake enhancers (MiCUps) efsevin, a gating modifier of the voltage\u2010dependent anion channel 2, and kaempferol, an agonist of the mitochondrial Ca<jats:sup>2+<\/jats:sup> uniporter. Both substances restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model and significantly suppressed arrhythmogenesis in freshly isolated ventricular cardiomyocytes from a CPVT mouse model as well as induced pluripotent stem cell derived cardiomyocytes from a CPVT patient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Taken together we identified ezetimibe and disulfiram as novel MiCUps and efficient suppressors of arrhythmogenesis and as such as, promising candidates for future preclinical and clinical studies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15630","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T10:54:23Z","timestamp":1626864863000},"page":"4518-4532","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca<sup>2+<\/sup> uptake and suppress cardiac arrhythmogenesis"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2384-3954","authenticated-orcid":false,"given":"Paulina","family":"Sander","sequence":"first","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC) Helmholtz Zentrum M\u00fcnchen  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria K.","family":"Schweitzer","sequence":"additional","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Wilting","sequence":"additional","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8412-3328","authenticated-orcid":false,"given":"Sophie M.","family":"Gutenthaler","sequence":"additional","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela M.","family":"Arduino","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC) Helmholtz Zentrum M\u00fcnchen  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Fischbach","sequence":"additional","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Dreizehnter","sequence":"additional","affiliation":[{"name":"I. Department of Medicine, Cardiology, Klinikum rechts der Isar Technische Universit\u00e4t M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Moretti","sequence":"additional","affiliation":[{"name":"I. Department of Medicine, Cardiology, Klinikum rechts der Isar Technische Universit\u00e4t M\u00fcnchen  Munich Germany"},{"name":"Partner Site Munich Heart Alliance (MHA) Deutsches Zentrum f\u00fcr Herz\u2010Kreislauf\u2010Forschung (DZHK)  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0323-7965","authenticated-orcid":false,"given":"Thomas","family":"Gudermann","sequence":"additional","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, LMU Munich  Munich Germany"},{"name":"Partner Site Munich Heart Alliance (MHA) Deutsches Zentrum f\u00fcr Herz\u2010Kreislauf\u2010Forschung (DZHK)  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1102-6500","authenticated-orcid":false,"given":"Fabiana","family":"Perocchi","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC) Helmholtz Zentrum M\u00fcnchen  Neuherberg Germany"},{"name":"Munich Cluster for Systems Neurology  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6657-0466","authenticated-orcid":false,"given":"Johann","family":"Schredelseker","sequence":"additional","affiliation":[{"name":"Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, LMU Munich  Munich Germany"},{"name":"Partner Site Munich Heart Alliance (MHA) Deutsches Zentrum f\u00fcr Herz\u2010Kreislauf\u2010Forschung (DZHK)  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2018.01.047"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1984.sp015281"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP274959"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.07.019"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-2797(01)00283-6"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10234"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000558"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu12020538"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.70.113006.100455"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000169067.51055.72"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00762725"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmr075"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.6.2979"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.755496"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.08.040"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2019.01.026"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10230"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.081"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-2918(01)80075-8"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2325"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000137798"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(82)90065-5"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0500269102"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_13_28_1","first-page":"2645","article-title":"Kaempferol is an anti\u2010inflammatory compound with activity towards NF\u2010\u03baB pathway proteins","volume":"35","author":"Kadioglu O.","year":"2015","journal-title":"Anticancer Research"},{"key":"e_1_2_13_29_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2015\/904142","article-title":"The dietary flavonoid kaempferol mediates anti\u2010inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular targets","volume":"2015","author":"Kim S. 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