A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment
A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment
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DOI：
10.1074/jbc.m113.509653
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发表时间：
2013-12-20
影响因子：
4.8
通讯作者：
Matsuda, Noriyuki
中科院分区：
文献类型：
--
作者：
Okatsu, Kei;Uno, Midori;Matsuda, Noriyuki
背景：PINK1在去极化的线粒体上发挥作用。然而，关于其机制的细节仍然有限。结果：我们揭示了由两个磷酸化的PINK1分子组成的高分子量复合体的形成，该复合体刺激了Parkin募集。结论：含PINK1二聚体的复合体对线粒体质量控制具有重要意义。意义：PINK1的分子过程使人联想到信号转导中的受体激酶二聚化。以散发性帕金森病为典型的帕金森病是一种普遍存在的神经退行性疾病。PINK1(PTEN诱导的推定激酶1)是一种线粒体丝氨酸/苏氨酸蛋白激酶，或Parkin是一种泛素蛋白连接酶，它的突变会导致家族性帕金森氏症。PINK1在受损线粒体上的积聚和自磷酸化导致Parkin的募集，最终触发蛋白酶体和自噬对受损线粒体的隔离和/或降解。然而，PINK1在线粒体膜电位(M)消散中的分子机制尚未完全阐明。在这里，我们通过基于荧光的技术表明，m降低后形成的PINK1复合体由两个PINK1分子组成，并与PINK1的分子间磷酸化相关。PINK1 S402a突变破坏了复合体的形成，削弱了Parkin在去极化线粒体上的募集。大多数与疾病相关的PINK1突变抑制了复合体的形成。综上所述，这些结果表明，包含二元PINK1的复合体的形成是Parkin重新募集到受损线粒体上的重要一步。
Background: PINK1 functions on depolarized mitochondria. However, details regarding its mechanism remain limited. Results: We reveal the formation of a high molecular weight complex composed of two phosphorylated PINK1 molecules that stimulates Parkin recruitment. Conclusion: The dimeric PINK1-containing complex is important for mitochondrial quality control. Significance: The PINK1 molecular process is reminiscent of receptor kinase dimerization in signal transduction.Parkinsonism typified by sporadic Parkinson disease is a prevalent neurodegenerative disease. Mutations in PINK1 (PTEN-induced putative kinase 1), a mitochondrial Ser/Thr protein kinase, or PARKIN, a ubiquitin-protein ligase, cause familial parkinsonism. The accumulation and autophosphorylation of PINK1 on damaged mitochondria results in the recruitment of Parkin, which ultimately triggers quarantine and/or degradation of the damaged mitochondria by the proteasome and autophagy. However, the molecular mechanism of PINK1 in dissipation of the mitochondrial membrane potential (m) has not been fully elucidated. Here we show by fluorescence-based techniques that the PINK1 complex formed following a decrease in m is composed of two PINK1 molecules and is correlated with intermolecular phosphorylation of PINK1. Disruption of complex formation by the PINK1 S402A mutation weakened Parkin recruitment onto depolarized mitochondria. The most disease-relevant mutations of PINK1 inhibit the complex formation. Taken together, these results suggest that formation of the complex containing dyadic PINK1 is an important step for Parkin recruitment onto damaged mitochondria.