Mitochondrial Dysfunction and Bioenergetic Deficiency in Cardiovascular Disease

Background: Mitochondria are essential organelles for maintaining cardiac energy homeostasis, producing over 90% of cellular ATP via oxidative phosphorylation. In cardiovascular disease (CVD), mitochondrial dysfunction represents a critical pathological hallmark that disrupts energy supply-demand balance, impairs redox signaling, and promotes cell death. Alterations in mitochondrial biogenesis, dynamics, and electron transport chain efficiency have been observed across a wide range of cardiac pathologies, including ischemic heart disease, heart failure, and cardiomyopathies. Methods and Results: This review synthesizes mechanistic insights into how mitochondrial dysfunction contributes to the onset and progression of CVD. Impaired mitochondrial respiration, reduced ATP production, and increased generation of reactive oxygen species (ROS) compromise cardiomyocyte contractility and viability. Defective mitophagy and aberrant fusion–fission dynamics further exacerbate mitochondrial injury, leading to accumulation of dysfunctional organelles and triggering inflammatory responses. Mitochondrial DNA (mtDNA) mutations and decreased expression of nuclear-encoded mitochondrial genes disrupt metabolic reprogramming and calcium homeostasis in failing hearts. Biochemical markers such as citrate synthase activity, complex I–IV enzymatic function, and mtDNA copy number have emerged as indicators of cardiac mitochondrial health. Therapeutic strategies aimed at restoring mitochondrial function include pharmacological agents targeting complex I (e.g., elamipretide), PGC-1α activators, antioxidants, metabolic modulators (e.g., trimetazidine), and gene therapy approaches to enhance mitochondrial quality control. Conclusion: Mitochondrial dysfunction is a central driver of bioenergetic failure and redox imbalance in cardiovascular disease.