Hypoxic postconditioning restores mitophagy against transient global cerebral ischemia via Parkin-induced posttranslational modification of TBK1
Hypoxic postconditioning restores mitophagy against transient global cerebral ischemia via Parkin-induced posttranslational modification of TBK1
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DOI：
10.1016/j.nbd.2023.106043
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发表时间：
2023-02-17
影响因子：
6.1
通讯作者：
Xu，En
中科院分区：
文献类型：
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作者：
Wen，Haixia;Zuo，Yunyan;Xu，En
据报道，缺氧后处理 (HPC) 可增强 Parkin 催化的线粒体泛素化，从而恢复海马 CA1 区的线粒体自噬，从而对抗短暂性全脑缺血 (tGCI)。然而，在 tGCI 后 HPC 介导的线粒体自噬过程中，导致泛素化线粒体最终被清除的分子机制尚不清楚。本研究旨在探讨HPC是否通过Parkin诱导的K63连接的多聚泛素化（K63-Ub）来激活雄性大鼠CA1区的肿瘤坏死因子相关因子家族成员相关核因子κB激活剂结合激酶1（TBK1）来恢复tGCI后的线粒体自噬。我们发现，HPC 维持了 TBK1 表达，促进线粒体中 p62 和 TBK1 磷酸化，并在 tGCI 后增强了它们向 CA1 中线粒体的募集。然而，这些作用被 TBK1 抑制剂 BX795 部分消除。 tGCI 后再灌注 26 小时，线粒体 TBK1 的 K63-Ub 受到干扰，而 HPC 可逆转这种情况。 HPC 诱导的线粒体 TBK1 K63-Ub 的维持在 Parkin 敲低下被 AAV 介导的 Prkn 小干扰 RNA 所抵消，同时伴随着对 TBK1 激活的抑制和线粒体 p62 磷酸化的减少。这项创新研究表明，HPC以Parkin依赖性方式维持TBK1的K63-Ub以促进TBK1磷酸化，然后磷酸化TBK1激活p62以恢复线粒体自噬，从而减轻tGCI后CA1中的神经元损伤。
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-mediatedPrknsmall-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.