The mitochondrial calcium homeostasis orchestra plays its symphony: Skeletal muscle is the guest of honor.

Skeletal muscle mitochondria are placed in close proximity of the sarcoplasmic reticulum (SR), the main intracellular Ca store. During muscle activity, excitation of sarcolemma and of T-tubule triggers the release of Ca from the SR initiating myofiber contraction. The rise in cytosolic Ca determines the opening of the mitochondrial calcium uniporter (MCU), the highly selective channel of the inner mitochondrial membrane (IMM), causing a robust increase in mitochondrial Ca uptake. The Ca-dependent activation of TCA cycle enzymes increases the synthesis of ATP required for SERCA activity. Thus, Ca is transported back into the SR and cytosolic [Ca] returns to resting levels eventually leading to muscle relaxation. In recent years, thanks to the molecular identification of MCU complex components, the role of mitochondrial Ca uptake in the pathophysiology of skeletal muscle has been uncovered. In this chapter, we will introduce the reader to a general overview of mitochondrial Ca accumulation. We will tackle the key molecular players and the cellular and pathophysiological consequences of mitochondrial Ca dyshomeostasis. In the second part of the chapter, we will discuss novel findings on the physiological role of mitochondrial Ca uptake in skeletal muscle. Finally, we will examine the involvement of mitochondrial Ca signaling in muscle diseases.