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.