Mitochondrial calcium homeostasis and atrial fibrillation: Mechanisms and therapeutic strategies review

Abstract

Atrial fibrillation (AF) is tightly linked to mitochondrial dysfunction, calcium (Ca²⁺) imbalance, and oxidative stress. Mitochondrial Ca²⁺ is essential for regulating metabolic enzymes, maintaining the tricarboxylic acid (TCA) cycle, supporting the electron transport chain (ETC), and producing ATP. Additionally, Ca²⁺ modulates oxidative balance by regulating antioxidant enzymes and reactive oxygen species (ROS) clearance. However, Ca²⁺ homeostasis disruptions, particularly overload, result in excessive ROS production, mitochondrial permeability transition pore (mPTP) opening, and oxidative stress-induced damage. These changes lead to mitochondrial dysfunction, Ca²⁺ leakage, and cardiomyocyte apoptosis, driving AF progression and atrial remodeling. Therapeutically, targeting mitochondrial Ca²⁺ homeostasis shows promise in mitigating AF. Moderate Ca²⁺ regulation enhances energy metabolism, stabilizes mitochondrial membrane potential, and bolsters antioxidant defenses by upregulating enzymes like superoxide dismutase and glutathione peroxidase. This reduces ROS generation and facilitates clearance. Proper Ca²⁺ levels also prevent electron leakage and promote mitophagy, aiding in damaged mitochondria removal and reducing ROS accumulation. Future strategies include modulating Ryanodine receptor 2 (RyR2), mitochondrial calcium uniporter (MCU), and sodium-calcium exchanger (NCLX) to control Ca²⁺ overload and oxidative damage. Addressing mitochondrial Ca²⁺ dynamics offers a compelling approach to breaking the cycle of Ca²⁺ overload, oxidative stress, and AF progression. Further research is needed to clarify the mechanisms of mitochondrial Ca²⁺ regulation and its role in AF pathogenesis. This knowledge will guide the development of innovative treatments to improve outcomes and quality of life for AF patients.