Acetylation of CPT1A reduces fatty acid oxidation and leads to dysfunctional renal tubular mitochondria in diabetic kidney disease

作者：Sun S, Liu S, Ruan S, Zhou H, Cui X, Lu N, Hong L, Lu M · 发表于：Biochemical pharmacology · 年份：2026 · DOI：10.1016/j.bcp.2025.117465 · 研究领域：Carnitine O-Palmitoyltransferase、Diabetic Nephropathies、Fatty Acids、Mitochondria、Kidney Tubules、Kidney Tubules, Proximal、Animals、Humans、Acetylation、Mice、Oxidation-Reduction、Male

Diabetic kidney disease (DKD), a major diabetic complication driving chronic and end-stage renal disease, involves disrupted proximal tubular energy metabolism. This study investigated the pathogenic role ofcarnitine palmitoyltransferase-1A (CPT1A) acetylation-a mitochondrial enzyme governing the rate-limiting step of fatty acid oxidation (FAO)-in DKD progression. Utilizingdb/dbmice to establishin vivoDKD models, we assessed renal fibrosis via histology/Western blotting and performedproteome-wide acetylation profiling. Parallelin vitroanalyses employed high-glucose (30 mM, 48 h)-treated human proximal renal tubular cells. Functional consequences oflysine 584 (K584) acetylationwere evaluated using lentiviral-mediated K584R point mutation. Results demonstrated: (1) Global protein hyperacetylation in DKD mice, with CPT1A identified as the most significantly hyperacetylated mitochondrial protein; (2) Downregulated CPT1A expression in renal tubular epithelia of both murine and human DKD tissues; (3) Association of CPT1A hyperacetylation with elevated α-smooth muscle actin, fibronectin, and reactive oxygen species (ROS), alongside reduced mitochondrial membrane potential, FAO, and fatty acid synthesis; (4) K584R mutation attenuated CPT1A acetylation, enhancing fatty acid synthase activity and FAO while reducing ROS and fibrosis markers. We conclude thatCPT1A acetylation at K584critically drives DKD pathogenesis and represents a promising biomarker/therapeutic target.