Mitochondrial metabolic reprogramming drives diabetic kidney disease progression: cell-specific mechanisms, metabolic memory, and targeted strategies.

Diabetic Kidney Disease (DKD), as a major microvascular complication of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease. Metabolic reprogramming is an important concept in cancer research, and the most classic example is the Warburg effect. This phenomenon has also been observed in DKD, suggesting that metabolic reprogramming also plays a significant role in DKD. Mitochondria are crucial in both catabolism and anabolism, making them the center of metabolic reprogramming research. Additionally, mitochondria are involved in methylation and acetylation modifications, potentially playing a vital role in "metabolic memory." Starting from the metabolic landscape of mitochondria in cells, this review discusses mitochondrial metabolic reprogramming in different types of renal and immune cells, providing insights into the mechanisms underlying "metabolic memory." In addition, we comprehensively summarize therapeutic strategies targeting mitochondrial metabolic reprogramming from both preclinical and clinical perspectives. Unlike previous studies that primarily focused on individual pathophysiological processes, this review integrates the intrinsic link between mitochondrial metabolic reprogramming and epigenetic modifications associated with "metabolic memory," thereby offering a novel interdisciplinary perspective for overcoming current therapeutic bottlenecks in DKD.