Hypoxic postconditioning restores mitophagy against transient global cerebral ischemia via Parkin-induced posttranslational modification of TBK1

Haixia Wen; Yunyan Zuo; Luxi Li; Lixuan Zhan; Jiahui Xue; Weiwen Sun; En Xu

doi:10.1016/j.nbd.2023.106043

Hypoxic postconditioning restores mitophagy against transient global cerebral ischemia via Parkin-induced posttranslational modification of TBK1

Neurobiol Dis. 2023 Apr:179:106043. doi: 10.1016/j.nbd.2023.106043. Epub 2023 Feb 15.

Authors

Haixia Wen¹, Yunyan Zuo², Luxi Li³, Lixuan Zhan², Jiahui Xue², Weiwen Sun², En Xu⁴

Affiliations

¹ Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 510260, PR China; Department of Neurology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
² Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 510260, PR China.
³ Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 510260, PR China; Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China.
⁴ Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 510260, PR China. Electronic address: enxu@163.net.

PMID: 36805078
DOI: 10.1016/j.nbd.2023.106043

Abstract

Hypoxic postconditioning (HPC) has been reported to enhance Parkin-catalyzed mitochondrial ubiquitination to restore mitophagy in hippocampal CA1 against transient global cerebral ischemia (tGCI). However, the molecular mechanism leading ubiquitinated mitochondria to final clearance during HPC-mediated mitophagy after tGCI is unclear. This study aims to investigate whether HPC restores mitophagy after tGCI through Parkin-induced K63-linked poly-ubiquitination (K63-Ub) to activate tumor necrosis factor associated factor family member associated nuclear factor κB activator -binding kinase 1 (TBK1) in CA1 of male rats. We found that HPC maintained TBK1 expression, promoted p62 and TBK1 phosphorylation in mitochondria, and enhanced their recruitments to mitochondria in CA1 after tGCI. However, these effects were partially abolished by TBK1 inhibitor BX795. K63-Ub of mitochondrial TBK1 was disturbed at 26 h of reperfusion after tGCI, which was reversed by HPC. The maintenance of K63-Ub of mitochondrial TBK1 induced by HPC was counteracted under Parkin knockdown with AAV-mediated Prkn small-interfering RNA, accompanied by the suppression on TBK1 activation and the reduction of mitochondrial p62 phosphorylation. This innovative study indicated that HPC maintained K63-Ub of TBK1 in a Parkin-dependent manner to promote TBK1 phosphorylation, and then phosphorylated TBK1 activated p62 to restore mitophagy, thereby alleviating neuronal damage in CA1 after tGCI.

Keywords: Hypoxic postconditioning; Neuroprotection; Parkin-dependent mitophagy; Posttranslational modification; TBK1; Transient global cerebral ischemia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ischemic Attack, Transient*
Male
Mitophagy*
Protein Processing, Post-Translational
Rats
Rats, Wistar
Ubiquitin-Protein Ligases / genetics

Substances

Ubiquitin-Protein Ligases
Tbk1 protein, rat
parkin protein