Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease.

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca 2+ ) in health and disease. In physiological states, Ca 2+ enters via the mitochondrial Ca 2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca 2+ homeostasis is critical: insufficient Ca 2+ impairs stress adaptation, and Ca 2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca 2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca 2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca 2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca 2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na + /Ca 2+ exchanger, and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca 2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca 2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.