Sirtuin 5-Mediated Lysine Desuccinylation Protects Mitochondrial Metabolism Following Subarachnoid Hemorrhage in Mice

Zhi-Peng Xiao, Department of Neurosurgery (Z.-P.X., T.L., Y.J., F.J., Q.H., X.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Tao Lv, Department of Neurosurgery (Z.-P.X., T.L., Y.J., F.J., Q.H., X.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Pin-Pin Hou, Central Laboratory (P.-P.H., L.G., Q.H.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Anatol Manaenko, National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, China (A.M.).
Yuandong Liu, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering East China Normal University, China (Y.L., Y.T.).
Yichao Jin, Department of Neurosurgery (Z.-P.X., T.L., Y.J., F.J., Q.H., X.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Li Gao, Central Laboratory (P.-P.H., L.G., Q.H.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Feng Jia, Department of Neurosurgery (Z.-P.X., T.L., Y.J., F.J., Q.H., X.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Yang Tian, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering East China Normal University, China (Y.L., Y.T.).
Peiying Li, Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China (P.L.).
John H. Zhang, Department of Physiology and Pharmacology, Loma Linda University, CA (J.H.Z.).Follow
Qin Hu, Department of Neurosurgery (Z.-P.X., T.L., Y.J., F.J., Q.H., X.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
Xiaohua Zhang, Department of Neurosurgery (Z.-P.X., T.L., Y.J., F.J., Q.H., X.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.

Document Type

Article

Publication Date

12-1-2021

Publication Title

Stroke

E-ISSN

1524-4628

Abstract

BACKGROUND AND PURPOSE: Sirt5 (Sirtuin 5) desuccinylates multiple metabolic enzymes and plays an important role in maintaining energy homeostasis. The goal of this study was to determine whether Sirt5-mediated desuccinylation restores the energy metabolism and protects brain against subarachnoid hemorrhage (SAH). METHODS: Male C57BL/6 or Sirt5 mice were used. The endovascular perforation SAH model was applied. Protein lysine succinylation in the brain cortex was examined using liquid chromatography-tandem mass spectrometry analysis. The brain metabolism was evaluated by measurement of brain pH as well as ATP and reactive oxygen species level. Neuronal cell death and neurobehavioral deficits were assessed 24 hours after SAH. The expression and desuccinylation activity of Sirt5, lysine succinylation of citrate synthase and ATP synthase subunits were investigated by Western blot, immunohistochemistry, and ELISA in SAH mice and patients. Furthermore, the benefits of resveratrol-mediated Sirt5 activation were investigated. RESULTS: A total of 211 lysine succinylation sites were differentially expressed on 170 proteins in mice brain after SAH. Thirty-nine percent of these succinylated proteins were localized in mitochondria and they are related to energy metabolism. SAH caused a decrease of Sirt5 expression and succinylated citrate synthase as well as the subunits of ATP synthase, subsequently lowered brain pH, reduced ATP and increased reactive oxygen species production, leading to neuronal cell death, and neurological deficits. Knockdown of Sirt5 aggravated SAH-induced effects, mentioned above. Administration of resveratrol resulted in activation of Sirt5. The activation was accompanied both with restoration of the mitochondrial metabolism and alleviation of early brain injury as well as with desuccinylating citrate synthase and ATP synthase. CONCLUSIONS: Protein lysine succinylation is a biochemical hallmark of metabolic crisis after SAH, and disruption of lysine succinylation through activation of Sirt5 might be a promising therapeutic strategy for the treatment of SAH.

Volume

52

Issue

12

First Page

4043

Last Page

4053

DOI

10.1161/STROKEAHA.121.034850

PubMed ID

34807744

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