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

Abstract

Skeletal muscle mitochondria are placed in close proximity of the sarcoplasmic reticulum (SR), the main intracellular Ca²⁺ store. During muscle activity, excitation of sarcolemma and of T-tubule triggers the release of Ca²⁺ from the SR initiating myofiber contraction. The rise in cytosolic Ca²⁺ 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 Ca²⁺ uptake. The Ca²⁺-dependent activation of TCA cycle enzymes increases the synthesis of ATP required for SERCA activity. Thus, Ca²⁺ is transported back into the SR and cytosolic [Ca²⁺] 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 Ca²⁺ uptake in the pathophysiology of skeletal muscle has been uncovered. In this chapter, we will introduce the reader to a general overview of mitochondrial Ca²⁺ accumulation. We will tackle the key molecular players and the cellular and pathophysiological consequences of mitochondrial Ca²⁺ dyshomeostasis. In the second part of the chapter, we will discuss novel findings on the physiological role of mitochondrial Ca²⁺ uptake in skeletal muscle. Finally, we will examine the involvement of mitochondrial Ca²⁺ signaling in muscle diseases.

Keywords: Central core disease; Mitochondrial Ca(2+) uptake; Mitochondrial calcium uniporter; Muscular dystrophy; Skeletal muscle.