Reactive Oxygen Species: Molecular Mechanisms, Cellular Targets, and Implications for Genomic Stability

Reactive oxygen species (ROS) are highly reactive molecules generated through endogenous metabolic pathways and exogenous environmental exposures. While essential for physiological processes-including cell signaling, proliferation, differentiation, immune defense, and neurotransmission-dysregulated ROS production contributes to oxidative stress and widespread biomolecular damage. This review outlines the major enzymatic and non-enzymatic mechanisms of ROS formation, emphasizing mitochondrial electron leakage, NADPH oxidase activity, and metal-catalyzed reactions. It further explores the impact of cold exposure, physical exercise, nutritional imbalance, and aging on ROS levels through alterations in mitochondrial function, calcium signaling, and antioxidant defenses. While ROS are vital for certain biological activities, the article also emphasizes their destructive potential. Particular attention is given to the vulnerability of mitochondrial DNA (mtDNA) and nuclear DNA to hydroxyl radical attack, resulting in base modifications, sugar lesions, tandem lesions, and DNA-protein cross-links. These lesions disrupt replication fidelity, impair DNA repair, and promote mutagenesis, ultimately threatening genomic stability. Finally, apoptosis is described as being modulated by ROS in a dose-dependent manner through the intrinsic, extrinsic, and ER-stress pathways, with the central role of p53 in determining cell fate being highlighted. Collectively, this review integrates current knowledge on ROS generation, physiological functions, stress-induced dysregulation, and the molecular mechanisms underlying oxidative damage, offering a comprehensive perspective on their implications for genomic integrity and disease development.