S‐sulfhydration of SIRT3 by hydrogen sulfide attenuates mitochondrial dysfunction in cisplatin‐induced acute kidney injury

Abstract

Clinical use of cisplatin, one of the most widely used common and effective chemotherapeutic agents, is limited by its side effects, particularly tubular injury–associated nephrotoxicity. Mitochondrial dysfunction is one of the main mechanisms contributing to cisplatin‐induced acute kidney injury (AKI), and sirtuin 3 (SIRT3) is closely associated with mitochondrial function and oxidative stress. Hydrogen sulfide (H2S) has powerful anti‐oxidative and anti‐inflammatory properties. We report that H2S alleviated cisplatin‐caused renal toxicity via SIRT3 activation and subsequent mitochondrial bioenergetics. Using a biotin switch assay, we show that H2S increased S‐sulfhydration of SIRT3 and induced deacetylation of its target proteins (OPA1, ATP synthase β and SOD2). These effects of H2S were associated with a reduction of mitochondrial fragment, an increase in ATP generation, and less oxidative injury. Notably, the S‐sulfhydration of SIRT3 induced by NaHS (a H2S donor) was abrogated when Cys256, Cys259, Cys280, and Cys283residues on SIRT3 (2 zinc finger domains) were mutated. Collectively, we demonstrate that H2S attenuates cisplatin‐induced AKI by preventing mitochondrial dysfunction via SIRT3 sulfhydrylation. Thus, SIRT3 may represent a new therapeutic target and H2S may be a potentially effective agent to limit cisplatin‐induced nephrotoxicity by activating SIRT3.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (Grant number 81370824 and 31571474), and China Postdoctoral Science Foundation (2017M620428).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.