Mitochondrial Dysfunction‐Evoked DHODH Acetylation is Involved in Renal Cell Ferroptosis during Cisplatin‐Induced Acute Kidney Injury

Abstract Several studies have observed renal cell ferroptosis during cisplatin‐induced acute kidney injury (AKI). However, the mechanism is not completely clear. In this study, oxidized arachidonic acid (AA) metabolites are increased in cisplatin‐treated HK‐2 cells. Targeted metabolomics showed that the end product of pyrimidine biosynthesis is decreased and the initiating substrate of pyrimidine biosynthesis is increased in cisplatin‐treated mouse kidneys. Mitochondrial DHODH, a key enzyme for pyrimidine synthesis, and its downstream product CoQH2, are downregulated. DHODH overexpression attenuated but DHODH silence exacerbated cisplatin‐induced CoQH2 depletion and lipid peroxidation. Mechanistically, renal DHODH acetylation is elevated in cisplatin‐exposed mice. Mitochondrial SIRT3 is reduced in cisplatin‐treated mouse kidneys and HK‐2 cells. Both in vitro SIRT3 overexpression and in vivo NMN supplementation attenuated cisplatin‐induced mitochondrial DHODH acetylation and renal cell ferroptosis. By contrast, Sirt3 knockout aggravated cisplatin‐induced mitochondrial DHODH acetylation and renal cell ferroptosis, which can not be attenuated by NMN. Additional experiments showed that cisplatin caused mitochondrial dysfunction and SIRT3 SUMOylation. Pretreatment with mitochondria‐target antioxidant MitoQ alleviated cisplatin‐caused mitochondrial dysfunction, SIRT3 SUMOylation, and DHODH acetylation. MitoQ pretreatment protected against cisplatin‐caused AKI and renal cell ferroptosis. Taken together, these results suggest that mitochondrial dysfunction‐evoked DHODH acetylation partially contributes to renal cell ferroptosis during cisplatin‐induced AKI.