Mitochondrial Dynamics in Aging Heart

Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show morphological alterations including cristae disorganization, swelling, and fragmentation, along with reduced OXPHOS efficiency. These defects increase proton leak, lower ATP production, and elevate reactive oxygen species (ROS), causing oxidative damage. Concurrent disruptions in mitochondrial fusion and fission further impair turnover and quality control, exacerbating mitochondrial dysfunction and cardiac decline. Serum response factor (SRF) signaling, a crucial regulator of cytoskeletal and metabolic gene expression, plays a key role in modulating mitochondrial function during cardiac aging. Dysregulation of SRF impairs mitochondrial adaptability, contributing to dysfunction. Additionally, reduced levels of nicotinamide adenine dinucleotide (NAD⁺) hinder sirtuin-dependent deacetylation, further compromising mitochondrial efficiency and stress resilience. These cumulative defects activate regulated cell death pathways, leading to cardiomyocyte loss, fibrosis, and impaired diastolic function. Mitochondrial dysfunction therefore serves as both a driver and amplifier of cardiac aging, accelerating the transition toward heart failure. This narrative review aims to provide a comprehensive overview of mitochondrial remodeling in the aging myocardium, examining the mechanistic links between mitochondrial dysfunction and myocardial injury. We also discuss emerging therapeutic strategies targeting mitochondrial bioenergetics and quality control as promising approaches to preserve cardiac function and extend cardiovascular health span in the aging population.