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.

Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.

While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.