Mitochondrial metabolic reprogramming and epigenetic modifications drive bidirectional regulation in renal tubular epithelial cellsMitochondrial Changes and Epigenetics Linked to Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Renal tubular epithelial cell (RTEC) injury is a core driver of DKD initiation and progression. Mitochondrial metabolic reprogramming and epigenetic modification are two core events in DKD pathogenesis, and their bidirectional crosstalk has become a frontier and hot research topic in the pathogenesis of DKD. At present, the specific molecular mechanisms of their bidirectional regulation remain incompletely elucidated. This narrative review collected literatures from PubMed, Web of Science and Embase up to March 2026. English original articles and reviews were included, whereas case reports, letters and non-English publications were excluded. We summarized the latest advances concerning the interaction between mitochondrial metabolic reprogramming and epigenetic modification in RTEC injury of DKD, focusing on their bidirectional molecular regulation. Key mitochondrial metabolic intermediates (acetyl-CoA, α-ketoglutarate (α-KG), nicotinamide adenine dinucleotide (NAD+)) act as substrates or cofactors of epigenetic enzymes to regulate DNA methylation, histone modifications, and noncoding RNA expression in RTECs. Epigenetic modifications in turn remodel mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation by regulating the expression of metabolism-related genes. This narrative review elaborates the closed-loop crosstalk between mitochondrial metabolism and epigenetics in tubular injury, highlights the therapeutic prospect of targeting this bidirectional regulatory axis, and provides novel theoretical evidence for revealing DKD pathogenesis and developing targeted intervention regimens.