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The divalent cation calcium (Ca2+) is best known in cardiomyocytes for its role in excitation-contraction coupling, where it triggers myosin-actin cross-bridge formation. However, Ca2+ regulates myriad fundamental processes in all cells. Among these are the activities of enzymes, channels, pumps, transcription, translation, motility, exocytosis, metabolism, growth, differentiation, and death.1 Mitochondria are the primary venue for some of these processes, such as metabolism and cell death. This raises a question that appears seemingly straightforward but has proven to be complex and contentious: How does Ca2+ get from its major storage depot, the sarcoplasmic reticulum (SR)/endoplasmic reticulum (ER), to mitochondria? In this issue of Circulation Research , Chen et al2 address this issue in cardiomyocytes.Article, see p 863Uptake of Ca2+ by mitochondria is critical for coupling the energy demands of cardiac work with metabolism.3 These demands can change on a beat-to-beat basis necessitating a messenger, such as Ca2+, with a rapid response time. The most intensive catabolism of substrates occurs in the mitochondrial matrix via the Krebs cycle, several rate-limiting enzymes of which are Ca2+-dependent. The phasic increases in cytosolic Ca2+ with each heart beat, which are more frequent or larger under conditions of increased energy demand (eg, increased heart rate or contractility), are sensed and averaged by the complex buffering system in mitochondria to accelerate cardiac metabolism through uptake of Ca2+ into the matrix.4The story of mitochondrial Ca2+ handling is long and convoluted, but a bolus of clarity was recently infused with the molecular identification of the mitochondrial Ca2+ uniporter (MCU) in the inner mitochondrial membrane5,6 (Figure). Ca2+ traverses the outer mitochondrial membrane through nonspecific high-conductance voltage-dependent anion channels to reach the intermembrane space. The MCU, which is …

Mitofusin 2 Joins the Sarcoplasmic Reticulum and Mitochondria at the Hip to Sustain Cardiac Energetics