Mitochondrial Dysfunction in the Development and Progression of Cardiometabolic Diseases: A Narrative Review

Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca2⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs.