The Parkinson's disease-associated gene PINK1 protects neurons from ischemic damage by decreasing mitochondrial translocation of the fission promoter Drp1
The Parkinson's disease-associated gene PINK1 protects neurons from ischemic damage by decreasing mitochondrial translocation of the fission promoter Drp1
复制标题
帕金森病相关基因 PINK1 通过减少裂变启动子 Drp1 的线粒体易位来保护神经元免受缺血性损伤
DOI：
10.1111/jnc.12340
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发表时间：
2013-12-01
影响因子：
4.7
通讯作者：
Dong, Qiang
中科院分区：
文献类型：
--
作者：
Zhao, Yanxin;Chen, Fangzhe;Dong, Qiang
我们以前的研究表明，PTEN诱导的新型激酶1（PINK1）敲低显著诱导线粒体片段化。虽然PINK1被证明与常染色体隐性遗传性帕金森综合征相关，并且其在这种慢性病理过程中的功能被广泛研究，但其在急性能量危机如缺血性卒中中的作用知之甚少。本研究采用氧糖剥夺（OGD）神经元模型，探讨PINK 1在脑缺血中的作用。人PINK1、两种PINK1突变体W437X和K219M或Pink1 shRNA在OGD之前使用慢病毒递送转导。我们的研究结果表明，野生型PINK1的过表达显着改善OGD诱导的细胞死亡和能量障碍，包括减少ATP的产生和线粒体膜电位的崩溃。PINK1过表达也逆转了OGD增加的线粒体碎片化，并抑制了线粒体分裂蛋白动力蛋白相关蛋白1（Drp1）从胞质溶胶到线粒体的易位。转导的突变体PINK1未能提供任何保护作用，而敲低Pink1显着增加OGD诱导的神经元损伤的严重性。重要的是，Drp1的抑制逆转了敲低Pink1对响应OGD的神经元死亡和ATP产生的影响。这项研究表明，PINK1通过减弱Drp1的线粒体易位来防止神经元的缺血性损伤，Drp1维持线粒体功能并抑制缺血诱导的线粒体分裂。这些新的发现暗示了PINK1调节的线粒体动力学在缺血性卒中病理学中的关键作用。
Our previous study has shown that PTEN-induced novel kinase 1 (PINK1) knocking down significantly induced mitochondrial fragmentation. Although PINK1 is proved to be associated with autosomal recessive parkinsonism and its function in this chronic pathological process is widely studied, its role in acute energy crisis such as ischemic stroke is poorly known. In this study by employing an oxygen-glucose deprivation (OGD) neuronal model, we explored the function of PINK1 in cerebral ischemia. Human PINK1, two PINK1 mutants W437X and K219M, or Pink1 shRNA were transduced before OGD using lentiviral delivery. Our results showed that over-expression of wild-type PINK1 significantly ameliorated OGD induced cell death and energy disturbance including reduced ATP generation and collapse of mitochondrial membrane potential. PINK1 over-expression also reversed OGD increased mitochondrial fragmentation, and suppressed the translocation of the mitochondrial fission protein dynamin-related protein 1 (Drp1) from the cytosol to the mitochondria. Transduction of the mutant PINK1 failed to provide any protective effect, while knockdown of Pink1 significantly increased the severity of OGD-induced neuronal damage. Importantly, inhibition of Drp1 reversed the effects of knocking down Pink1 on neuronal death and ATP production in response to OGD. This study demonstrates that PINK1 prevents ischemic damage in neurons by attenuating mitochondrial translocation of Drp1, which maintains mitochondrial function and inhibits ischemia-induced mitochondrial fission. These novel findings implicate a pivotal role of PINK1 regulated mitochondrial dynamics in the pathology of ischemic stroke.