Mitochondrial calcium and the regulation of metabolism in the heart

Consumption of adenosine triphosphate (ATP) by the heart can change dramatically as the energetic demands increase from a period of rest to strenuous activity. Mitochondrial ATP production is central to this metabolic response since the heart relies largely on oxidative phosphorylation as its source of intracellular ATP. Significant evidence has been acquired indicating that Ca2 + plays a critical role in regulating ATP production by the mitochondria. Here the evidence that the Ca2 + concentration in the mitochondrial matrix ([Ca2 +]m) plays a pivotal role in regulating ATP production by the mitochondria is critically reviewed and aspects of this process that are under current active investigation are highlighted. Importantly, current quantitative information on the bidirectional Ca2 + movement across the inner mitochondrial membrane (IMM) is examined in two parts. First, we review how Ca2 + influx into the mitochondrial matrix depends on the mitochondrial Ca2 + channel (i.e., the mitochondrial calcium uniporter or MCU). This discussion includes how the MCU open probability (PO) depends on the cytosolic Ca2 + concentration ([Ca2 +]i) and on the mitochondrial membrane potential (ΔΨm). Second, we discuss how steady-state [Ca2 +]m is determined by the dynamic balance between this MCU-based Ca2 + influx and mitochondrial Na+/Ca2 + exchanger (NCLX) based Ca2 + efflux. These steady-state [Ca2 +]m levels are suggested to regulate the metabolic energy supply due to Ca2 +-dependent regulation of mitochondrial enzymes of the tricarboxylic acid cycle (TCA), the proteins of the electron transport chain (ETC), and the F1F0 ATP synthase itself. We conclude by discussing the roles played by [Ca2 +]m in influencing mitochondrial responses under pathological conditions. This article is part of a Special Issue entitled "Mitochondria: From BasicMitochondrial Biology to Cardiovascular Disease."