Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease: From Molecular Mechanisms to Biomarkers and Targeted Therapies

Chronic kidney disease (CKD) represents a major global health challenge, affecting more than 10% of the population and contributing substantially to morbidity and premature mortality. Growing evidence identifies oxidative stress and mitochondrial dysfunction as central drivers of renal injury and disease progression across diverse etiologies. The kidney is one of the most mitochondria-rich organs in the body, reflecting the high bioenergetic demands required for tubular reabsorption and metabolic homeostasis. Disruption of mitochondrial oxidative phosphorylation, excessive production of reactive oxygen species (ROS), and impaired mitochondrial quality control mechanisms promote tubular injury, inflammation, and fibrosis. In particular, dysfunction of the electron transport chain, activation of NADPH oxidase isoforms—especially NOX4—and alterations in mitochondrial dynamics create a vicious cycle of oxidative damage and bioenergetic failure. Emerging evidence highlights the importance of mitochondrial quality control pathways, including fusion–fission balance, PINK1/Parkin-mediated mitophagy, and mitochondrial biogenesis regulated by PGC-1α and TFAM. Recent studies have also identified additional mechanisms linking mitochondrial dysfunction to CKD progression, including ferroptosis, epigenetic regulation of mitochondrial genes, and mitochondrial DNA release acting as damage-associated molecular patterns that activate innate immune pathways. At the clinical level, redox and mitochondrial biomarkers—such as F2-isoprostanes, 8-hydroxy-2′-deoxyguanosine, advanced oxidation protein products, and circulating mitochondrial DNA—may improve early diagnosis and risk stratification. Therapeutically, both established nephroprotective drugs and emerging mitochondria-targeted interventions aim to restore mitochondrial homeostasis and represent promising strategies for slowing CKD progression.