Integrative Insights Into Mitochondrial Dysfunction and Organelle Crosstalk in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease and is driven in large part by early, sustained mitochondrial dysfunction, which promotes metabolic reprogramming, oxidative stress and inflammation that accelerate glomerular and tubular injury. We review recent mechanistic and translational advances linking mitochondrial dysfunction and organelle crosstalk to DKD progression. We synthesize evidence across four interrelated mitochondrial axes-metabolic reprogramming, altered fission-fusion dynamics, defective mitophagy, and mtDNA release-and highlight mitochondria-ER contacts (MAMs) as a nexus integrating redox signaling and calcium homeostasis. Preclinical studies indicate that interventions restoring mitochondrial biogenesis, rebalancing dynamics, enhancing selective mitophagy and preserving mtDNA attenuate glomerular and tubular injury. Clinically, several approved agents (metformin, SGLT2 inhibitors, finerenone, GLP-1RAs) exert renoprotective effects involving mitochondrial pathways; deconvolution of multi-component formulations, targeted antioxidants, metabolic activators and fission inhibitors expand therapeutic options, while organelle-level approaches such as mitochondrial transplantation are emergent. We propose a translational framework that links redox-centered mitochondrial mechanisms to actionable therapeutic strategies for DKD.