PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation
PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation
复制标题
在线粒体自噬过程中，PINK1和BECN1在线粒体相关膜上重新定位，促进er -线粒体系结和自噬体的形成
DOI：
10.1080/15548627.2016.1277309
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Valente, Enza Maria
中科院分区：
文献类型：
--
作者：
Gelmetti, Vania;De Rosa, Priscilla;Valente, Enza Maria
有丝分裂是一种高度专门化的过程，通过宏观自噬/自噬途径去除功能障碍或多余的线粒体，旨在保护细胞免受线粒体代谢紊乱和诱导细胞凋亡的破坏。PINK1是一种在常染色体隐性遗传性帕金森病中突变的神经保护蛋白，通过选择性地聚集在去极化的线粒体上，促进PARK2/Parkin向线粒体移位，参与了有丝分裂的激活。虽然这些步骤已经被深入描述，但关于自噬小体在有丝分裂刺激下形成的过程和位置还知之甚少。先前的一项研究报道，在饥饿诱导的自噬中，前自噬蛋白BECN1/Beclin1(我们先前证明与PINK1相互作用)重新定位于内质网(ER)和线粒体之间的特定接触区域，称为线粒体相关膜(MAM)，自噬小体起源于该区域。在这里，我们发现，在有丝分裂刺激后，自噬小体也在MAM形成；此外，内源性PINK1和BECN1都被发现在MAM重新定位，在那里它们促进了代表自噬小体前体的ER-线粒体接触位点的增强和omegasome的形成。MAM诱导有丝分裂后，PARK2表达也增强。然而，PINK1沉默可独立于PARK2抑制BECN1在MAM的聚集，提示PINK1在调节丝裂原吞噬中的新作用。MAM最近被认为与许多关键的细胞事件有关。在这一点上，观察到的PINK1在MAM的普遍定位可以很好地解释该蛋白的其他神经保护活性，如调节线粒体钙水平、线粒体动力学和细胞凋亡。
Mitophagy is a highly specialized process to remove dysfunctional or superfluous mitochondria through the macroautophagy/autophagy pathway, aimed at protecting cells from the damage of disordered mitochondrial metabolism and apoptosis induction. PINK1, a neuroprotective protein mutated in autosomal recessive Parkinson disease, has been implicated in the activation of mitophagy by selectively accumulating on depolarized mitochondria, and promoting PARK2/Parkin translocation to them. While these steps have been characterized in depth, less is known about the process and site of autophagosome formation upon mitophagic stimuli. A previous study reported that, in starvation-induced autophagy, the proautophagic protein BECN1/Beclin1 (which we previously showed to interact with PINK1) relocalizes at specific regions of contact between the endoplasmic reticulum (ER) and mitochondria called mitochondria-associated membranes (MAM), from which the autophagosome originates. Here we show that, following mitophagic stimuli, autophagosomes also form at MAM; moreover, endogenous PINK1 and BECN1 were both found to relocalize at MAM, where they promoted the enhancement of ER-mitochondria contact sites and the formation of omegasomes, that represent autophagosome precursors. PARK2 was also enhanced at MAM following mitophagy induction. However, PINK1 silencing impaired BECN1 enrichment at MAM independently of PARK2, suggesting a novel role for PINK1 in regulating mitophagy. MAM have been recently implicated in many key cellular events. In this light, the observed prevalent localization of PINK1 at MAM may well explain other neuroprotective activities of this protein, such as modulation of mitochondrial calcium levels, mitochondrial dynamics, and apoptosis.