Mitochondrial Ca²⁺ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling

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.