Sirtuin 5 alleviates excessive mitochondrial fission via desuccinylation of ATPase inhibitory factor 1 in sepsis-induced acute kidney injury.

Abstract

ABSTRACT:

Sepsis-induced acute kidney injury (SAKI) poses a significant clinical challenge with high morbidity and mortality. Excessive mitochondrial fission has been identified as the central pathogenesis of sepsis-associated organ damage, which is also implicated in the early stages of SAKI. Sirtuin 5 (SIRT5) has emerged as a central regulator of cellular mitochondrial function; however, its role in the regulation of sepsis-induced excessive mitochondrial fission in kidney and the underlying mechanism remains unclear.In this study, SAKI was modeled in mice through cecal ligation and puncture (CLP), and in human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide (LPS), to mimic the cell SAKI model. Our findings revealed that septic mice with a SIRT5 knockout (SIRT5 KO) exhibited shortened survival times and elevated levels of renal injury compared to wild-type (WT) mice, suggesting the significant involvement of SIRT5 in SAKI pathophysiology. Additionally, we observed that SIRT5 depletion led to increased renal mitochondrial fission, while the use of a mitochondrial fission inhibitor (Mdivi-1) reversed the detrimental effects caused by SIRT5 depletion, emphasizing the pivotal role of SIRT5 in preventing excessive mitochondrial fission. In vitro experiments demonstrated that the overexpression of SIRT5 effectively mitigated the adverse effects of LPS on HK-2 cells viability and mitochondrial fission. Conversely, downregulation of SIRT5 decreased HK-2 cells viability and exacerbated LPS-induced mitochondrial fission. Mechanistically, the protective function of SIRT5 may be in part, ascribed to its desuccinylating action on ATPase inhibitory factor 1 (ATPIF1).In conclusion, this study provides novel insights into the underlying mechanisms of SAKI, suggesting the possibility of identifying future drug targets in terms of improved mitochondrial dynamics by SIRT5.

• Authors: Jiaxin Li, Yi Yao, Xiaobao Lei, Jingna Bao, Sheng An, Hongbin Hu, Tong Sha, Qiaobing Huang, Tao Li, Zhenhua Zeng, Xiang Wang, Shumin Cai
• Journal: Shock (Augusta, Ga.) (Shock) (May 15 2024) ISSN: 1540-0514 [Electronic] United States
• PMID: 38754030 (Publication Type: Journal Article)
• Copyright: Copyright © 2024 by the Shock Society.