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Mitochondrial Ca\n 2+<\/jats:sup>\n transport is essential for initiating an adrenergic response. However, continuous stimulation might lead to mitochondrial Ca\n 2+<\/jats:sup>\n overload and dysfunction within cardiac tissue. This study investigates the role of mitochondrial Ca\n 2+<\/jats:sup>\n in lethal arrhythmogenesis and the effects of its modulation.\n <\/jats:p>\n <\/jats:sec>\n \n Experimental Approach<\/jats:title>\n \n Male C57BL\/6 mice were administered either Ru360 (oxo\u2010bridged dinuclear ruthenium ammine complex) a potent and selective mitochondrial Ca\n 2+<\/jats:sup>\n transport inhibitor, or normal saline via intravenous injection. A baseline electrocardiogram (ECG) was recorded, followed by subcutaneous administration of isoprenaline. The ECG was monitored for an additional 20\u2009min, after which cardiomyocytes and mitochondria were isolated for further characterization studies.\n <\/jats:p>\n <\/jats:sec>\n \n Key Results<\/jats:title>\n \n Isoprenaline administration led to ventricular tachycardia and fibrillation, but Ru360 pretreatment successfully prevented these arrhythmias. Mitochondria from isoprenaline\u2010treated hearts showed higher Ca\n 2+<\/jats:sup>\n content, indicating overload that compromised mitochondrial function and membrane integrity, evidenced by decreased respiratory control, reduced Ca\n 2+<\/jats:sup>\n retention capacity and diminished membrane potential. Isoprenaline also increased oxidative stress, illustrated by elevated peroxide production, electron leak and acute oxidative modifications, and erratic cellular Ca\n 2+<\/jats:sup>\n dynamics. This mitochondrial dysfunction correlated with a decreased respirasome activity, but not a difference in respirasome abundance quantified by complexome profiling, which was prevented by Ru360 pretreatment.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Mitochondrial Ca\n 2+<\/jats:sup>\n overload significantly contributes to arrhythmias by disrupting respirasome function and increasing oxidative stress, impairing cellular Ca\n 2+<\/jats:sup>\n dynamics. Modulating mitochondrial Ca\n 2+<\/jats:sup>\n transport might be a promising strategy for developing innovative antiarrhythmic therapies.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bph.70253","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T07:49:52Z","timestamp":1763192992000},"page":"1404-1426","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mitochondrial Ca\n 2+<\/sup>\n overload is a pivotal risk factor for lethal ventricular arrhythmias due to the oxidation of mitochondrial respirasome and energetic failure"],"prefix":"10.1111","volume":"183","author":[{"given":"Felipe de Jes\u00fas","family":"Salazar\u2010Ram\u00edrez","sequence":"first","affiliation":[{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud C\u00e1tedra de Cardiolog\u00eda y Medicina Vascular Monterrey Mexico"},{"name":"Hospital Zambrano\u2010Hellion San Pedro 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