Abstract
Mitochondria are the sites of oxidative metabolism in eukaryotes where the metabolites of sugars, fats, and amino acids are oxidized to harvest energy. Notably, mitochondria store Ca2+ and work in synergy with organelles such as the endoplasmic reticulum and extracellular matrix to control the dynamic balance of Ca2+ concentration in cells. Mitochondria are the vital organelles in heart tissue. Mitochondrial Ca2+ homeostasis is particularly important for maintaining the physiological and pathological mechanisms of the heart. Mitochondrial Ca2+ homeostasis plays a key role in the regulation of cardiac energy metabolism, mechanisms of death, oxygen free radical production, and autophagy. The imbalance of mitochondrial Ca2+ balance is closely associated with cardiac remodeling. The mitochondrial Ca2+ uniporter (mtCU) protein complex is responsible for the uptake and release of mitochondrial Ca2+ and regulation of Ca2+ homeostasis in mitochondria and consequently, in cells. This review summarizes the mechanisms of mitochondrial Ca2+ homeostasis in physiological and pathological cardiac remodeling and the regulatory effects of the mitochondrial calcium regulatory complex on cardiac energy metabolism, cell death, and autophagy, and also provides the theoretical basis for mitochondrial Ca2+ as a novel target for the treatment of cardiovascular diseases.
Highlights
Mitochondria are called “power stations” because it is here that cells perform aerobic respiration and produce energy
This review provides an overview of mitochondrial Ca2+ homeostasis in regulating cardiac
Entry into mitochondria, including mitochondrial calcium uniporter dominant negative β (MCUb), MICU2, MCU-regulator 1 (MCUR1), essential monomolecular carrier (MCU) regulator (EMRE), and Solute carriers—solute carrier 25A23 (SLC25A23) (Mg2+/ATPPi Porter), were discovered [129,141–144]. These findings suggest that the uptake of Ca2+ by mitochondria is mediated by a macromolecular structure, known as the mitochondrial Ca2+ uniporter, which can be inhibited by lanthanide or ruthenium red [65]
Summary
Mitochondria are called “power stations” because it is here that cells perform aerobic respiration and produce energy. Ca2+ plays a key role in the excitation–contraction coupling of the myocardium [28] and flows into the cytoplasm from the extracellular space through voltage-gated L-type Ca2+ channels, triggering the opening of RyR2 on the SR toward the t-tubules, promoting the release of Ca2+ in the SR (i.e., Ca2+ induced Ca2+ release), causing the transient increase in the intracellular calcium concentration, which is called “calcium transient”. MAM is a complex formed by the precise regulation of Ca2+ exchange between ER and mitochondria through the recruitment of different mitochondria-related proteins and plays an important role in maintaining mitochondrial Ca2+ homeostasis and regulating the function and survival of cells [196] (Figure 3). Because mitochondrial Ca2+ is a key regulator involved in many biological functions, the IP3R-GRP75-VDAC-MCU complex may play an important regulatory role in various cellular functions. Its activation results in the release of a large amount of Ca2+ by the sarcoplasmic reticulum and the transient increase of cytoplasmic Ca2+
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