Sirt3 inhibits cerebral ischemia-reperfusion injury through normalizing Wnt/β-catenin pathway and blocking mitochondrial fission

Zhao, Hao; Luo, Yongchun; Chen, Lihua; Zhang, Zhenhai; Shen, Chunsen; Li, Yunjun; Xu, Ruxiang

doi:10.1007/s12192-018-0917-y

Original Paper
Published: 03 June 2018

Sirt3 inhibits cerebral ischemia-reperfusion injury through normalizing Wnt/β-catenin pathway and blocking mitochondrial fission

Hao Zhao¹,
Yongchun Luo¹,
Lihua Chen¹,
Zhenhai Zhang¹,
Chunsen Shen¹,
Yunjun Li¹ &
Ruxiang Xu¹

Cell Stress and Chaperones volume 23, pages 1079–1092 (2018)Cite this article

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Abstract

Cerebral ischemia-reperfusion injury (IRI) potentiates existing brain damage and increases mortality and morbidity via poorly understood mechanisms. The aim of our study is to investigate the role of Sirtuin 3 (Sirt3) in the development and progression of cerebral ischemia-reperfusion injury with a focus on mitochondrial fission and the Wnt/β-catenin pathway. Our data indicated that Sirt3 was downregulated in response to cerebral IRI. However, the overexpression of Sirt3 reduced the brain infarction area and repressed IRI-mediated neuron apoptosis. Functional assays demonstrated that IRI augmented mitochondrial fission, which induced ROS overproduction, redox imbalance, mitochondrial pro-apoptotic protein leakage, and caspase-9-dependent cell death pathway activation. However, the overexpression of Sirt3 blocked mitochondrial fission and induced pro-survival signals in neurons subjected to IRI. At the molecular level, our data further illustrated that the Wnt/β-catenin pathway is required for the neuroprotection exerted by Sirt3 overexpression. Wnt/β-catenin pathway activation via inhibiting β-catenin phosphorylation attenuates mitochondrial fission and mitochondrial apoptosis. Collectively, our data show that cerebral IRI is associated with Sirt3 downregulation, Wnt/β-catenin pathway phosphorylated inactivation, and mitochondrial fission initiation, causing neurons to undergo caspase-9-dependent cell death. Based on this, strategies for enhancing Sirt3 activity and activating the Wnt/β-catenin pathway could be therapeutic targets for treating cerebral ischemia-reperfusion injury.

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Funding

This study was supported by a grant from the National Natural Science Foundation of China (grant No. 81100917) and Beijing Nova program (Z171100001117096).

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Department of Neurosurgery, PLA Army General Hospital, No.5 Nanmencang Hutong, Dongcheng District, Beijing, 100730, China
Hao Zhao, Yongchun Luo, Lihua Chen, Zhenhai Zhang, Chunsen Shen, Yunjun Li & Ruxiang Xu

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Hao Zhao
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Yongchun Luo
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Lihua Chen
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Zhenhai Zhang
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Chunsen Shen
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Yunjun Li
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Ruxiang Xu
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Contributions

HZ, YCL, and LHC conceived the research; ZHZ, CSS, YJL, and RXX performed the experiments; all authors participated in discussing and revising the manuscript.

Corresponding author

Correspondence to Ruxiang Xu.

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The animal study was performed in accordance with the Declaration of Helsinki. All experimental protocols were approved by the Ethics Committee of Department of neurosurgery, PLA army general hospital, Beijing, China, Beijing, China. The ethics reference number: SCSSJN20112.

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The authors declare that they have no conflict of interest.

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Zhao, H., Luo, Y., Chen, L. et al. Sirt3 inhibits cerebral ischemia-reperfusion injury through normalizing Wnt/β-catenin pathway and blocking mitochondrial fission. Cell Stress and Chaperones 23, 1079–1092 (2018). https://doi.org/10.1007/s12192-018-0917-y

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Received: 18 April 2018
Revised: 15 May 2018
Accepted: 19 May 2018
Published: 03 June 2018
Issue Date: September 2018
DOI: https://doi.org/10.1007/s12192-018-0917-y

Keywords

Cerebral ischemia-reperfusion (IR) injury
Mitochondrial fission
Apoptosis
Wnt/β-catenin pathways