Epigenetic and mitochondrial regulation in kidney disease: emerging mechanisms and therapeutic opportunities

Abstract

Renal fibrosis is an important pathogenic characteristic in the course of chronic kidney disease, driven by intricate interactions between mitochondrial failure and epigenetic control. The kidney is highly energy dependent and hence particularly vulnerable to mitochondrial disturbances such as decreased oxidative phosphorylation, mitochondrial reactive oxygen species (ROS) overproduction, reduced ATP production and mitochondrial DNA damage. Such changes induce oxidative stress and inflammatory reactions leading to tubular damage and fibrotic remodeling. Epigenetic processes such as DNA methylation, histone modifications and non-coding RNAs influence gene-expression programmes linked to inflammation, death, epithelial plasticity and extracellular-matrix deposition. Indeed, recent research indicates that there is reciprocal crosstalk between mitochondrial metabolism and epigenetic regulation, with metabolites such as NAD+, acetyl-CoA, α-ketoglutarate, succinate, fumarate and lactate, as well as ROS signaling, as mediators of this crosstalk. This interaction may also enhance inflammatory and fibrotic systems that drive chronic kidney disease progression. This mito-epigenetic axis has emerged as a therapeutic target. Potential strategies to mitigate renal fibrosis include SIRT1/PGC-1α signaling, AMPK activation, NRF2 antioxidant responses, epigenetic regulators (e.g., HDACs and DNMTs), and mitochondria-targeted antioxidants. Hence, this review analyses evidence according to illness, renal cell type, immunological state and translational maturity rather than considering mitochondrial and epigenetic alterations as uniform whole-kidney processes.