Mitochondrial metabolism and dynamics in the development of diabetic kidney disease

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide, affecting over 40% of individuals with diabetes. Despite advances in glycemic control and renin-angiotensin system blockade, effective therapeutic strategies remain limited. A narrative review was synthesized from research papers using PubMed, Wiley Online Library, ScienceDirect, Cochrane Library, Springer, and other sources, published between 2000 and 2025 with logical combinations of appropriate keywords and Medical Subject Headings. Emerging evidence implicates mitochondrial dysfunction as the central pathogenic mechanism underlying DKD progression. Mitochondria govern critical cellular processes, comprising energy metabolism, reactive oxygen species homeostasis, and cell survival. In DKD, hyperglycemia-induced metabolic stress compromises mitochondrial oxidative phosphorylation, enhances reactive oxygen species production, damages mitochondrial DNA, as well as disrupts mitochondrial dynamics through aberrant fission, fusion, and mitophagy processes. These alterations occur early in the pathogenesis of disease and affect multiple renal cell types, particularly proximal tubular epithelial cells and podocytes. Recent studies have identified key molecular regulators of mitochondrial quality control, including PTEN-induced putative kinase 1/Parkin-mediated mitophagy, dynamin-related protein 1-driven fission, and peroxisome proliferator-activated receptor gamma coactivator 1-αlpha-dependent biogenesis, as potential therapeutic targets. Novel therapies targeting mitochondrial dysfunction, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, mitochondria-targeted antioxidants, and metabolic modulators, have shown promise in preclinical and clinical studies. This paper synthesizes recent understanding of mitochondrial metabolism and dynamics in DKD pathogenesis and evaluates emerging mitochondria-directed therapeutic strategies. This review concludes that only SGLT2 inhibitors are the only class of drugs with robust randomized controlled trial evidence to date and other emerging therapeutic options require further clinical validation.