Sirtuin 5‐Mediated Desuccinylation of ALDH2 Alleviates Mitochondrial Oxidative Stress Following Acetaminophen‐Induced Acute Liver Injury

Author:

Yu Qiwen123ORCID,Zhang Jiakai4ORCID,Li Jiye123ORCID,Song Yaodong123ORCID,Pan Jie4ORCID,Mei Chaopeng123ORCID,Cui Mengwei123ORCID,He Qianqian123ORCID,Wang Haifeng123ORCID,Li Huihui123ORCID,Cheng Bo123ORCID,Zhang Yan123ORCID,Guo Wenzhi45ORCID,Zhu Changju123ORCID,Chen Sanyang123ORCID

Affiliation:

1. Department of Emergency Medicine The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450052 China

2. Henan Medical Key Laboratory of Emergency and Trauma Research Zhengzhou Henan 450052 China

3. Henan Emergency and Trauma Medicine Engineering Research Center Zhengzhou Henan 450052 China

4. Department of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450052 China

5. Henan Key Laboratory for Digestive Organ Transplantation The First Affiliated Hospital of  Zhengzhou University Zhengzhou Henan 450052 China

Abstract

AbstractAcetaminophen (APAP) overdose is a major cause of drug‐induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development of various liver diseases. However, its involvement in APAP‐induced acute liver injury (AILI) remains unclear. The present study aimed to explore the role of SIRT5 in AILI. SIRT5 expression is dramatically downregulated by APAP administration in mouse livers and AML12 hepatocytes. SIRT5 deficiency not only exacerbates liver injury and the inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, the opposite pathological and biochemical changes are observed in mice with SIRT5 overexpression. Mechanistically, quantitative succinylome analysis and site mutation experiments revealed that SIRT5 desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 and maintained the enzymatic activity of ALDH2, resulting in the suppression of inflammation and mitochondrial oxidative stress. Furthermore, succinylation of ALDH2 at lysine 385 abolished its protective effect against AILI, and the protective effect of SIRT5 against AILI is dependent on the desuccinylation of ALDH2 at K385. Finally, virtual screening of natural compounds revealed that Puerarin promoted SIRT5 desuccinylase activity and further attenuated AILI. Collectively, the present study showed that the SIRT5‐ALDH2 axis plays a critical role in AILI progression and might be a strategy for therapeutic intervention.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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