Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats.
Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats.
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缺氧后处理通过 PINK1/Parkin 诱导的成年大鼠线粒体泛素化促进线粒体自噬，对抗短暂性全脑缺血
DOI：
10.1038/s41419-021-03900-8
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发表时间：
2021-06-18
影响因子：
9
通讯作者：
Xu E
中科院分区：
文献类型：
--
作者：
Wen H;Li L;Zhan L;Zuo Y;Li K;Qiu M;Li H;Sun W;Xu E
线粒体自噬通过选择性清除功能障碍的线粒体减轻脑缺血后的神经元损伤。磷酸酶和张力蛋白同源物（PTEN）诱导的推定激酶1（PINK 1）/帕金森蛋白介导的线粒体自噬是最常见的线粒体自噬类型。然而，PINK 1/Parkin介导的线粒体自噬在8%O2低氧后处理（HPC）诱导的短暂性全脑缺血（tGCI）耐受中的作用知之甚少。因此，我们的目的是测试的假设，HPC介导的PINK 1/Parkin诱导线粒体泛素化，促进线粒体自噬，从而发挥神经保护作用，在海马CA 1区对tGCI。我们发现，在tGCI后再灌注后期，线粒体清除受到干扰，HPC逆转，证明在HPC后CA 1中的线粒体外膜20同源物（TOMM 20），线粒体内膜23（TIMM 23）和热休克蛋白60（HSP 60）的减少。此外，HPC还可进一步增加tGCI后海马CA 1区神经元线粒体LC 3 II/I比值，促进线粒体吞噬体的形成。腹腔注射溶酶体抑制剂氯喹（CQ）或侧脑室注射线粒体自噬抑制剂（Mdivi-1）可阻断HPC诱导的线粒体更新和tGCI后的神经保护作用。我们还发现HPC激活了tGCI后的PINK 1/Parkin通路，表现为线粒体PINK 1和Parkin的增加以及CA 1线粒体泛素化的促进。此外，小干扰RNA（siRNA）抑制PINK 1或Parkin表达可抑制PINK 1/Parkin通路的激活，阻碍线粒体清除，减弱HPC诱导的神经保护作用，而PINK 1过表达可促进PINK 1/Parkin介导的线粒体自噬，减轻tGCI后CA 1区神经元损伤。综上所述，本研究的新发现是HPC通过促进PINK 1/Parkin依赖性通路介导的线粒体自噬来诱导针对tGCI的神经保护。
Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.
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DOI：
10.1083/jcb.201401070
发表时间：
2014-09-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ashrafi G;Schlehe JS;LaVoie MJ;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
8.3
作者：
PULSINELLI, WA;BRIERLEY, JB
通讯作者：
BRIERLEY, JB
柚皮苷通过抑制过氧亚硝酸盐介导的线粒体自噬激活减轻脑缺血再灌注损伤
影响因子：
5.1
作者：
Feng, Jinghan;Chen, Xingmiao;Shen, Jiangang
通讯作者：
Shen, Jiangang
DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
通讯作者：
Tanaka K
Parkin对泛素 - 蛋白酶体系统的广泛激活对于线粒体至关重要。
影响因子：
3.5
作者：
Chan NC;Salazar AM;Pham AH;Sweredoski MJ;Kolawa NJ;Graham RL;Hess S;Chan DC
通讯作者：
Chan DC