Calcium Regulation of Mitochondrial Metabolism

Mitochondrial ATP production dynamically adapts to cellular energy demands, with calcium (Ca 2+ ) playing a crucial regulatory role. In this review, we critically evaluate the evidence for intramitochondrial Ca 2+ ([Ca 2+ ] m ) sensitivity in key energy metabolic pathways, highlighting the [Ca 2+ ] m dependence of specific mitochondrial systems. We also address the metabolic consequences of [Ca 2+ ] m -sensitive ATP production, particularly its effects on the utilization of specific macronutrients that fuel ATP production. Next, we discuss the primary Ca 2+ entry pathway into the matrix, the mitochondrial Ca 2+ uniporter (MCU), its macromolecular complex structure (MCUcx), and allosteric regulation by Ca 2+ . Key to this regulation are specific auxiliary subunits, along with the influence of mitochondrial inner membrane architecture. While the Ca 2+ signaling plays an important role, it does not fully explain the scope for regulating ATP production. Emerging evidence suggests that additional signaling systems operating alongside the Ca 2+ signaling contribute to the control of mitochondrial ATP production, a topic requiring further investigation.