{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:11:09Z","timestamp":1790424669467,"version":"4.1.0"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Obesity and diabetes increase the risk of arrhythmia and sudden cardiac death. However, the molecular mechanisms of arrhythmia caused by metabolic abnormalities are not well understood. We hypothesized that mitochondrial dysfunction caused by high fat diet (HFD) promotes ventricular arrhythmia. Based on our previous work showing that saturated fat causes calcium handling abnormalities in cardiomyocytes, we hypothesized that mitochondrial calcium uptake contributes to HFD-induced mitochondrial dysfunction and arrhythmic events. For experiments, we used mice with conditional cardiac-specific deletion of the mitochondrial calcium uniporter (<jats:italic>Mcu<\/jats:italic>), which is required for mitochondrial calcium uptake, and littermate controls. Mice were used for in vivo heart rhythm monitoring, perfused heart experiments, and isolated cardiomyocyte experiments. MCU KO mice are protected from HFD-induced long QT, inducible ventricular tachycardia, and abnormal ventricular repolarization. Abnormal repolarization may be due, at least in part, to a reduction in protein levels of voltage gated potassium channels. Furthermore, isolated cardiomyocytes from MCU KO mice exposed to saturated fat are protected from increased reactive oxygen species (ROS), mitochondrial dysfunction, and abnormal calcium handling. Activation of calmodulin-dependent protein kinase (CaMKII) corresponds with the increase in arrhythmias in vivo. Additional experiments showed that CaMKII inhibition protects cardiomyocytes from the mitochondrial dysfunction caused by saturated fat. Hearts from transgenic CaMKII inhibitor mice were protected from inducible ventricular tachycardia after HFD. These studies identify mitochondrial dysfunction caused by calcium overload as a key mechanism of arrhythmia during HFD. This work indicates that MCU and CaMKII could be therapeutic targets for arrhythmia caused by metabolic abnormalities.<\/jats:p>","DOI":"10.1038\/s41598-021-97449-3","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T10:02:46Z","timestamp":1631095366000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet"],"prefix":"10.1038","volume":"11","author":[{"given":"Leroy C.","family":"Joseph","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael V.","family":"Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin A.","family":"Homan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"Gowen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma Mahesh R.","family":"Avula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris N.","family":"Goulbourne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine Y.","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Elrod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Morrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,8]]},"reference":[{"key":"97449_CR1","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.3389\/fphys.2018.01847","volume":"9","author":"EA Homan","year":"2018","unstructured":"Homan, E. A., Reyes, M. V., Hickey, K. T. & Morrow, J. P. Clinical overview of obesity and diabetes mellitus as risk factors for atrial fibrillation and sudden cardiac death. Front. Physiol. 9, 1847 (2018).","journal-title":"Front. Physiol."},{"key":"97449_CR2","doi-asserted-by":"publisher","first-page":"2096","DOI":"10.1161\/01.CIR.0000065223.21530.11","volume":"107","author":"CM Albert","year":"2003","unstructured":"Albert, C. M. et al. Prospective study of sudden cardiac death among women in the United States. Circulation 107, 2096\u20132101 (2003).","journal-title":"Circulation"},{"key":"97449_CR3","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1161\/01.CIR.99.15.1978","volume":"99","author":"X Jouven","year":"1999","unstructured":"Jouven, X., Desnos, M., Guerot, C. & Ducimetiere, P. Predicting sudden death in the population: The Paris Prospective Study I. Circulation 99, 1978\u20131983 (1999).","journal-title":"Circulation"},{"key":"97449_CR4","doi-asserted-by":"publisher","first-page":"595","DOI":"10.2459\/JCM.0b013e3282f2c9d0","volume":"9","author":"A Filippi","year":"2008","unstructured":"Filippi, A. et al. Out of hospital sudden cardiac death in Italy: A population-based case-control study. J. Cardiovasc. Med. 9, 595\u2013600 (2008).","journal-title":"J. Cardiovasc. Med."},{"key":"97449_CR5","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1016\/j.hrthm.2011.06.031","volume":"8","author":"E Hookana","year":"2011","unstructured":"Hookana, E. et al. Causes of nonischemic sudden cardiac death in the current era. Heart Rhythm 8, 1570\u20131575 (2011).","journal-title":"Heart Rhythm"},{"key":"97449_CR6","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.hrthm.2010.10.034","volume":"8","author":"AH Ramirez","year":"2011","unstructured":"Ramirez, A. H. et al. Modulators of normal electrocardiographic intervals identified in a large electronic medical record. Heart Rhythm 8, 271\u2013277 (2011).","journal-title":"Heart Rhythm"},{"key":"97449_CR7","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1001\/archinte.1987.00370100039008","volume":"147","author":"FH Messerli","year":"1987","unstructured":"Messerli, F. H., Nunez, B. D., Ventura, H. O. & Snyder, D. W. Overweight and sudden death: Increased ventricular ectopy in cardiopathy of obesity. Arch. Intern. Med. 147, 1725\u20131728 (1987).","journal-title":"Arch. Intern. Med."},{"key":"97449_CR8","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1177\/000331970005100202","volume":"51","author":"A Zemva","year":"2000","unstructured":"Zemva, A. & Zemva, Z. Ventricular ectopic activity, left ventricular mass, hyperinsulinemia, and intracellular magnesium in normotensive patients with obesity. Angiology 51, 101\u2013106 (2000).","journal-title":"Angiology"},{"key":"97449_CR9","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.hrthm.2007.04.019","volume":"4","author":"E Watanabe","year":"2007","unstructured":"Watanabe, E. et al. Prognostic significance of circadian variability of RR and QT intervals and QT dynamicity in patients with chronic heart failure. Heart Rhythm 4, 999\u20131005 (2007).","journal-title":"Heart Rhythm"},{"key":"97449_CR10","doi-asserted-by":"publisher","first-page":"434","DOI":"10.2337\/diabetes.53.2.434","volume":"53","author":"PM Okin","year":"2004","unstructured":"Okin, P. M., Devereux, R. B., Lee, E. T., Galloway, J. M. & Howard, B. V. Electrocardiographic repolarization complexity and abnormality predict all-cause and cardiovascular mortality in diabetes: The strong heart study. Diabetes 53, 434\u2013440 (2004).","journal-title":"Diabetes"},{"key":"97449_CR11","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1038\/sj.ijo.0803233","volume":"30","author":"E Seyfeli","year":"2006","unstructured":"Seyfeli, E., Duru, M., Kuvandik, G., Kaya, H. & Yalcin, F. Effect of obesity on P-wave dispersion and QT dispersion in women. Int. J. Obes. 30, 957\u2013961 (2006).","journal-title":"Int. J. Obes."},{"key":"97449_CR12","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1136\/bmj.316.7133.745","volume":"316","author":"AA Naas","year":"1998","unstructured":"Naas, A. A. et al. QT and QTc dispersion are accurate predictors of cardiac death in newly diagnosed non-insulin dependent diabetes: Cohort study. BMJ 316, 745\u2013746 (1998).","journal-title":"BMJ"},{"key":"97449_CR13","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1016\/0735-1097(95)00279-8","volume":"26","author":"K Wei","year":"1995","unstructured":"Wei, K., Dorian, P., Newman, D. & Langer, A. Association between QT dispersion and autonomic dysfunction in patients with diabetes mellitus. J. Am. Coll. Cardiol. 26, 859\u2013863 (1995).","journal-title":"J. Am. Coll. Cardiol."},{"key":"97449_CR14","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1161\/01.CIR.97.5.467","volume":"97","author":"MC de Bruyne","year":"1998","unstructured":"de Bruyne, M. C. et al. QTc dispersion predicts cardiac mortality in the elderly: The Rotterdam Study. Circulation 97, 467\u2013472 (1998).","journal-title":"Circulation"},{"key":"97449_CR15","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1161\/CIRCEP.110.960658","volume":"4","author":"R Panikkath","year":"2011","unstructured":"Panikkath, R. et al. Prolonged Tpeak-to-tend interval on the resting ECG is associated with increased risk of sudden cardiac death. Circ. Arrhythm Electrophysiol. 4, 441\u2013447 (2011).","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"97449_CR16","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1053\/euhj.1998.1094","volume":"19","author":"H Elming","year":"1998","unstructured":"Elming, H. et al. The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens. Eur. Heart J. 19, 1391\u20131400 (1998).","journal-title":"Eur. Heart J."},{"key":"97449_CR17","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.amjcard.2012.03.045","volume":"110","author":"R Mukerji","year":"2012","unstructured":"Mukerji, R. et al. Effect of weight loss after bariatric surgery on left ventricular mass and ventricular repolarization in normotensive morbidly obese patients. Am. J. Cardiol. 110, 415\u2013419 (2012).","journal-title":"Am. J. Cardiol."},{"key":"97449_CR18","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1161\/CIRCRESAHA.107.160457","volume":"101","author":"LS Szczepaniak","year":"2007","unstructured":"Szczepaniak, L. S., Victor, R. G., Orci, L. & Unger, R. H. Forgotten but not gone: The rediscovery of fatty heart, the most common unrecognized disease in America. Circ. Res. 101, 759\u2013767 (2007).","journal-title":"Circ. Res."},{"key":"97449_CR19","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/j.jacc.2006.03.048","volume":"48","author":"D Mozaffarian","year":"2006","unstructured":"Mozaffarian, D., Prineas, R. J., Stein, P. K. & Siscovick, D. S. Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. J. Am. Coll. Cardiol. 48, 478\u2013484 (2006).","journal-title":"J. Am. Coll. Cardiol."},{"key":"97449_CR20","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1161\/hc3201.094151","volume":"104","author":"X Jouven","year":"2001","unstructured":"Jouven, X., Charles, M. A., Desnos, M. & Ducimetiere, P. Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation 104, 756\u2013761 (2001).","journal-title":"Circulation"},{"key":"97449_CR21","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/S0140-6736(68)92163-6","volume":"1","author":"MF Oliver","year":"1968","unstructured":"Oliver, M. F., Kurien, V. A. & Greenwood, T. W. Relation between serum-free-fatty acids and arrhythmias and death after acute myocardial infarction. Lancet 1, 710\u2013714 (1968).","journal-title":"Lancet"},{"key":"97449_CR22","doi-asserted-by":"publisher","first-page":"498","DOI":"10.3945\/ajcn.112.040287","volume":"96","author":"SE Chiuve","year":"2012","unstructured":"Chiuve, S. E. et al. Dietary fat quality and risk of sudden cardiac death in women. Am. J. Clin. Nutr. 96, 498\u2013507 (2012).","journal-title":"Am. J. Clin. Nutr."},{"key":"97449_CR23","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/j.metabol.2009.10.026","volume":"59","author":"RN Lemaitre","year":"2010","unstructured":"Lemaitre, R. N. et al. Endogenous red blood cell membrane fatty acids and sudden cardiac arrest. Metabolism 59, 1029\u20131034 (2010).","journal-title":"Metabolism"},{"key":"97449_CR24","doi-asserted-by":"publisher","first-page":"549","DOI":"10.3389\/fphys.2019.00549","volume":"10","author":"JP Morrow","year":"2019","unstructured":"Morrow, J. P., Akar, F. G. & Aromolaran, A. S. Editorial: Arrhythmogenic substrates in diabetes and obesity. Front. Physiol. 10, 549 (2019).","journal-title":"Front. Physiol."},{"key":"97449_CR25","doi-asserted-by":"publisher","first-page":"518","DOI":"10.3389\/fphys.2018.01518","volume":"9","author":"Z Ilkan","year":"2018","unstructured":"Ilkan, Z. & Akar, F. G. The mitochondrial translocator protein and the emerging link between oxidative stress and arrhythmias in the diabetic heart. Front. Physiol. 9, 518 (2018).","journal-title":"Front. Physiol."},{"key":"97449_CR26","doi-asserted-by":"publisher","first-page":"e007573","DOI":"10.1161\/CIRCEP.119.007573","volume":"12","author":"LC Joseph","year":"2019","unstructured":"Joseph, L. C. et al. Dietary saturated fat promotes arrhythmia by activating NOX2 (NADPH Oxidase 2). Circ. Arrhythm Electrophysiol. 12, e007573 (2019).","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"97449_CR27","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.celrep.2015.06.017","volume":"12","author":"TS Luongo","year":"2015","unstructured":"Luongo, T. S. et al. The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. Cell Rep. 12, 23\u201334 (2015).","journal-title":"Cell Rep."},{"key":"97449_CR28","doi-asserted-by":"publisher","first-page":"e0145750","DOI":"10.1371\/journal.pone.0145750","volume":"11","author":"LC Joseph","year":"2016","unstructured":"Joseph, L. C. et al. Inhibition of NADPH oxidase 2 (NOX2) prevents oxidative stress and mitochondrial abnormalities caused by saturated fat in cardiomyocytes. PLoS ONE 11, e0145750 (2016).","journal-title":"PLoS ONE"},{"key":"97449_CR29","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1475-925X-4-11","volume":"4","author":"RH Clayton","year":"2005","unstructured":"Clayton, R. H. & Holden, A. V. Dispersion of cardiac action potential duration and the initiation of re-entry: a computational study. Biomed. Eng. Online 4, 11 (2005).","journal-title":"Biomed. Eng. Online"},{"key":"97449_CR30","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/nm1215","volume":"11","author":"R Zhang","year":"2005","unstructured":"Zhang, R. et al. Calmodulin kinase II inhibition protects against structural heart disease. Nat. Med. 11, 409\u2013417 (2005).","journal-title":"Nat. Med."},{"key":"97449_CR31","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/nature12537","volume":"502","author":"JR Erickson","year":"2013","unstructured":"Erickson, J. R. et al. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502, 372\u2013376 (2013).","journal-title":"Nature"},{"key":"97449_CR32","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nm.4284","volume":"23","author":"A Vikram","year":"2017","unstructured":"Vikram, A. et al. Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel. Nat. Med. 23, 361\u2013367 (2017).","journal-title":"Nat. Med."},{"key":"97449_CR33","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.celrep.2015.06.002","volume":"12","author":"JQ Kwong","year":"2015","unstructured":"Kwong, J. Q. et al. The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Rep. 12, 15\u201322 (2015).","journal-title":"Cell Rep."},{"key":"97449_CR34","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1161\/CIRCRESAHA.108.175919","volume":"103","author":"T Liu","year":"2008","unstructured":"Liu, T. & O\u2019Rourke, B. Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circ. Res. 103, 279\u2013288 (2008).","journal-title":"Circ. Res."},{"key":"97449_CR35","first-page":"8","volume":"7","author":"A Xie","year":"2018","unstructured":"Xie, A. et al. Mitochondrial Ca(2+) influx contributes to arrhythmic risk in nonischemic cardiomyopathy. J. Am. Heart Assoc. 7, 8 (2018).","journal-title":"J. Am. Heart Assoc."},{"key":"97449_CR36","doi-asserted-by":"publisher","first-page":"11389","DOI":"10.1073\/pnas.1513047112","volume":"112","author":"G Santulli","year":"2015","unstructured":"Santulli, G., Xie, W., Reiken, S. R. & Marks, A. R. Mitochondrial calcium overload is a key determinant in heart failure. Proc. Natl. Acad. Sci. USA 112, 11389\u201311394 (2015).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"97449_CR37","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1016\/j.hrthm.2016.05.002","volume":"13","author":"LC Joseph","year":"2016","unstructured":"Joseph, L. C. et al. Mitochondrial oxidative stress during cardiac lipid overload causes intracellular calcium leak and arrhythmia. Heart Rhythm 13, 1699\u20131706 (2016).","journal-title":"Heart Rhythm"},{"key":"97449_CR38","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1161\/CIRCRESAHA.118.312708","volume":"123","author":"S Dey","year":"2018","unstructured":"Dey, S., DeMazumder, D., Sidor, A., Foster, D. B. & O\u2019Rourke, B. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ. Res. 123, 356\u2013371 (2018).","journal-title":"Circ. Res."},{"key":"97449_CR39","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/nature11444","volume":"491","author":"ML Joiner","year":"2012","unstructured":"Joiner, M. L. et al. CaMKII determines mitochondrial stress responses in heart. Nature 491, 269\u2013273 (2012).","journal-title":"Nature"},{"key":"97449_CR40","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1113\/JP276766","volume":"598","author":"AG Nickel","year":"2020","unstructured":"Nickel, A. G. et al. CaMKII does not control mitochondrial Ca2+ uptake in cardiac myocytes. J. Physiol. 598, 1361\u20131376 (2020).","journal-title":"J. Physiol."},{"key":"97449_CR41","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.yjmcc.2013.03.007","volume":"59C","author":"H Huang","year":"2013","unstructured":"Huang, H. et al. Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels. J. Mol. Cell. Cardiol. 59C, 151\u2013158 (2013).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"97449_CR42","doi-asserted-by":"publisher","first-page":"3527","DOI":"10.1172\/JCI25371","volume":"115","author":"FG Akar","year":"2005","unstructured":"Akar, F. G., Aon, M. A., Tomaselli, G. F. & O\u2019Rourke, B. The mitochondrial origin of postischemic arrhythmias. J. Clin. Invest. 115, 3527\u20133535 (2005).","journal-title":"J. Clin. Invest."},{"key":"97449_CR43","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.yjmcc.2012.07.015","volume":"55","author":"GW Dorn 2nd","year":"2013","unstructured":"Dorn, G. W. 2nd. & Maack, C. SR and mitochondria: Calcium cross-talk between kissing cousins. J. Mol. Cell Cardiol. 55, 42\u201349 (2013).","journal-title":"J. Mol. Cell Cardiol."},{"key":"97449_CR44","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.cmet.2014.12.001","volume":"21","author":"JQ Kwong","year":"2015","unstructured":"Kwong, J. Q. & Molkentin, J. D. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab. 21, 206\u2013214 (2015).","journal-title":"Cell Metab."},{"key":"97449_CR45","doi-asserted-by":"publisher","first-page":"11427","DOI":"10.1038\/srep11427","volume":"5","author":"W Xie","year":"2015","unstructured":"Xie, W. et al. Mitochondrial oxidative stress promotes atrial fibrillation. Sci. Rep. 5, 11427 (2015).","journal-title":"Sci. Rep."},{"key":"97449_CR46","doi-asserted-by":"publisher","first-page":"2812","DOI":"10.1161\/CIRCULATIONAHA.111.056309","volume":"124","author":"JP Morrow","year":"2011","unstructured":"Morrow, J. P. et al. Mice with cardiac overexpression of peroxisome proliferator-activated receptor gamma have impaired repolarization and spontaneous fatal ventricular arrhythmias. Circulation 124, 2812\u20132821 (2011).","journal-title":"Circulation"},{"key":"97449_CR47","doi-asserted-by":"publisher","first-page":"H753","DOI":"10.1152\/ajpheart.00404.2012","volume":"303","author":"JI Laughner","year":"2012","unstructured":"Laughner, J. I., Ng, F. S., Sulkin, M. S., Arthur, R. M. & Efimov, I. R. Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes. Am. J. Physiol. Heart Circ. Physiol. 303, H753-765 (2012).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"97449_CR48","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.1161\/CIRCULATIONAHA.113.004742","volume":"129","author":"RP Martins","year":"2014","unstructured":"Martins, R. P. et al. Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation. Circulation 129, 1472\u20131482 (2014).","journal-title":"Circulation"},{"key":"97449_CR49","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1172\/jci.insight.94248","volume":"2","author":"LC Joseph","year":"2017","unstructured":"Joseph, L. C. et al. Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function. JCI Insight 2, 17 (2017).","journal-title":"JCI Insight"},{"key":"97449_CR50","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1152\/ajpendo.00418.2011","volume":"302","author":"MJ Watt","year":"2012","unstructured":"Watt, M. J., Hoy, A. J., Muoio, D. M. & Coleman, R. A. Distinct roles of specific fatty acids in cellular processes: implications for interpreting and reporting experiments. Am. J. Physiol. Endocrinol. Metab. 302, E1-3 (2012).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"97449_CR51","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/978-1-60761-411-1_4","volume":"594","author":"E Eruslanov","year":"2010","unstructured":"Eruslanov, E. & Kusmartsev, S. Identification of ROS using oxidized DCFDA and flow-cytometry. Methods Mol. Biol. 594, 57\u201372 (2010).","journal-title":"Methods Mol. Biol."},{"key":"97449_CR52","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1016\/S0006-3495(98)77642-8","volume":"75","author":"DN Bowser","year":"1998","unstructured":"Bowser, D. N., Minamikawa, T., Nagley, P. & Williams, D. A. Role of mitochondria in calcium regulation of spontaneously contracting cardiac muscle cells. Biophys. J. 75, 2004\u20132014 (1998).","journal-title":"Biophys. J."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97449-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97449-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97449-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T14:18:58Z","timestamp":1699453138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-97449-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,8]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["97449"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-97449-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,8]]},"assertion":[{"value":"5 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17808"}}