Mitochondrial calcium regulation of cardiac metabolism in health and disease

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca²⁺) in health and disease. In physiological states, Ca²⁺ enters via the mitochondrial Ca²⁺ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca²⁺ homeostasis is critical: insufficient Ca²⁺ impairs stress adaptation, while Ca²⁺ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca²⁺ 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 Ca²⁺ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca²⁺ 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, Ca²⁺ 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⁺-Ca²⁺ exchanger and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca²⁺ 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 Ca²⁺ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.