Mitochondrial ATP sensitive potassium channel (mitoKATP) in cardiac pathophysiology

Mitochondrial potassium homeostasis is crucial for organelle structure, redox balance, and cardioprotection, largely mediated by the mitochondrial ATP-sensitive potassium channel (mitoKATP). This channel, composed of MITOK and MITOSUR subunits, is a well-established target of pharmacological preconditioning against ischemia/reperfusion (I/R) injury. However, its role in baseline and stress-induced cardiac function remains unclear. We investigated cardiac structure and function in wild-type (WT) and Mitok knockout (Mitok-KO) mice. At baseline, electron microscopy revealed normal mitochondrial number and size, though Mitok-KO mitochondria displayed wider cristae. Isolated mitochondria and cardiomyocytes from both genotypes exhibited comparable ROS levels, respiration, Ca²⁺ handling, and contractility. Echocardiography confirmed preserved cardiac structure and function in Mitok-KO mice under resting conditions. Under stress, distinct responses emerged. In doxorubicin-induced cardiotoxicity, Mitok-KO mice were protected, maintaining myocardial function compared to WT. Conversely, following acute β-adrenergic injury (isoproterenol), Mitok-KO hearts exhibited incomplete recovery of systolic function, indicating reduced cardiac reserve. Chronic adrenergic stimulation induced hypertrophy to a similar extent in both genotypes, showing that Mitok is not required for hypertrophic remodeling. Pharmacological studies revealed that diazoxide, a non-selective mitoKATP opener, prevented hypertrophy in both WT and Mitok-KO cells, suggesting mitoKATP-independent effects. In contrast, a novel mitochondria-targeted channel opener suppressed hypertrophy only in WT cells, confirming specificity and higher potency. Importantly, this compound provided robust protection in vitro against anoxia/reoxygenation and doxorubicin-induced cardiomyocyte death, including in human iPSC-derived cardiomyocytes, and retained efficacy when applied at reperfusion. In conclusion, genetic ablation of Mitok does not impair baseline mitochondrial or cardiac function but alters responses to stress. Selective pharmacological activation of mitoKATP confers cardioprotection, highlighting the channel as a promising therapeutic target for cardiac injury.