Free Mitochondrial DNA and Mitophagy Dysfunction in Diabetic Kidney Disease: A Central Mitochondrial–Inflammatory Axis Driving Progressive Renal Injury

Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease and end-stage renal failure worldwide despite significant advances in glucose-lowering and renoprotective therapies. Emerging evidence identifies mitochondrial dysfunction as a central pathogenic mechanism linking metabolic stress to chronic inflammation and progressive renal injury. In the diabetic kidney, hyperglycemia, lipotoxicity, and oxidative stress impair mitochondrial quality control pathways, particularly mitophagy, a targeted mitochondrial degradation pathway, leading to the accumulation of dysfunctional mitochondria and increased mitochondrial reactive oxygen species production. A critical consequence of mitochondrial damage is the cytosolic release of mitochondrial DNA (mtDNA), which acts as a potent damage-associated molecular pattern and can activate innate immune pathways, including cGAS–STING, NLRP3 inflammasome, and Toll-like receptor 9 signaling. Persistent mtDNA-driven immune activation promotes sterile inflammation, cellular senescence, extracellular matrix remodeling, and renal fibrosis, thereby establishing a vicious cycle that accelerates DKD progression. In this review, we examine the emerging role of the mitochondrial DNA–inflammatory axis in DKD, highlighting the interplay between mitophagy dysfunction, mtDNA release, innate immune activation, and fibrotic remodeling. We further discuss the potential of circulating and urinary mtDNA as biomarkers of disease activity and evaluate therapeutic strategies targeting mitochondrial quality control, oxidative stress, and mtDNA-sensing pathways. Collectively, these findings position mtDNA as a critical mechanistic link between mitochondrial dysfunction and chronic inflammation, and support targeting the mitochondrial–immune axis as a promising strategy for precision therapies in DKD.