Pathological glutaminolysis induces mitochondrial injury via OPA1 glutamylation in renal fibrosis

The promotion of repair in proximal renal tubular epithelial cells (PTEC) or the prevention of repair failure has been suggested as a beneficial strategy for mitigating the progression of chronic kidney disease (CKD). However, effective interventions to halt CKD progression and subsequent renal fibrosis remain elusive. In this study, we identified aberrant activation of glutaminolysis during renal fibrosis, which results in glutamate accumulation within PTEC. Inhibition of glutamine metabolism reduces glutamate accumulation, enhances the glutamylation of the dynamin-related protein OPA1, and exacerbates mitochondrial damage. By mutating the glutamylation site to stabilize OPA1 and prevent its glutamylation, we were able to mitigate mitochondrial damage and alleviate renal fibrosis. Mechanistically, Forkhead box K1 (FOXK1) facilitates glutaminolysis by transcriptionally regulating the key enzyme solute carrier family 1 member 5 (SLC1A5) and suppressing the expression of SLC7A11, thereby promoting glutamate accumulation. Overall, the damaged PTEC relies on glutamine catabolism, and its inhibition provides a promising strategy for the prevention and treatment of CKD.