Reprogramming the Mitochondrion in Atherosclerosis: Targets for Vascular Protection

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, with a substantial proportion of events occurring prematurely. Atherosclerosis (AS), the central driver of cardiovascular pathology, results from the convergence of metabolic disturbances, vascular inflammation, and organelle dysfunction. Among intracellular organelles, mitochondria have emerged as critical regulators of vascular homeostasis. Beyond their canonical role in adenosine triphosphate (ATP) production, mitochondrial dysfunction-including impaired mitochondrial oxidative phosphorylation (OXPHOS), excessive generation of reactive oxygen species (ROS), accumulation of mitochondrial DNA (mtDNA) damage, dysregulated dynamics, and defective mitophagy-contributes to endothelial dysfunction, vascular smooth muscle cell (VSMC) phenotypic switching, macrophage polarization, and ultimately plaque initiation and destabilization. These insights have established the rationale for mitochondrial "reprogramming"-that is, the restoration of mitochondrial homeostasis through interventions enhancing biogenesis, dynamics, and quality control-as a novel therapeutic paradigm. Interventions that enhance mitochondrial biogenesis, restore mitophagy, and rebalance fission-fusion dynamics are showing promise in preclinical models of vascular injury. A growing array of translational strategies-including small-molecule activators such as resveratrol and Mitoquinone (MitoQ), gene-based therapies, and nanoparticle-mediated drug delivery systems-are under active investigation. This review synthesizes current mechanistic knowledge on mitochondrial dysfunction in ASand critically appraises therapeutic approaches aimed at vascular protection through mitochondrial reprogramming.