PTEN-induced putative kinase 1(PINK1)与 TOM 复合物和替代的细胞内膜结合在募集和激活 E3 连接酶 Parkin 中的作用。

Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin.

机构信息

Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

出版信息

Dev Cell. 2012 Feb 14;22(2):320-33. doi: 10.1016/j.devcel.2011.12.014. Epub 2012 Jan 25.

Abstract

Mutations in the mitochondrial kinase PINK1 and the cytosolic E3 ligase Parkin can cause Parkinson's disease. Damaged mitochondria accumulate PINK1 on the outer membrane where, dependent on kinase activity, it recruits and activates Parkin to induce mitophagy, potentially maintaining organelle fidelity. How PINK1 recruits Parkin is unknown. We show that endogenous PINK1 forms a 700 kDa complex with the translocase of the outer membrane (TOM) selectively on depolarized mitochondria whereas PINK1 ectopically targeted to the outer membrane retains association with TOM on polarized mitochondria. Inducibly targeting PINK1 to peroxisomes or lysosomes, which lack a TOM complex, recruits Parkin and activates ubiquitin ligase activity on the respective organelles. Once there, Parkin induces organelle selective autophagy of peroxisomes but not lysosomes. We propose that the association of PINK1 with the TOM complex allows rapid reimport of PINK1 to rescue repolarized mitochondria from mitophagy, and discount mitochondrial-specific factors for Parkin translocation and activation.

摘要

线粒体激酶 PINK1 和细胞质 E3 连接酶 Parkin 的突变可导致帕金森病。受损的线粒体在外膜上积累 PINK1,在那里,它依赖激酶活性招募并激活 Parkin 诱导线粒体自噬,可能维持细胞器的保真度。然而,PINK1 如何招募 Parkin 尚不清楚。我们发现内源性 PINK1 与外膜转位酶(TOM)形成一个 700 kDa 的复合物,这种复合物只选择性地存在于去极化的线粒体上,而 PINK1 异位靶向到外膜上时,在极化的线粒体上仍与 TOM 保持关联。可诱导地将 PINK1 靶向到过氧化物酶体或溶酶体,这些细胞器缺乏 TOM 复合物,会招募 Parkin 并在相应的细胞器上激活泛素连接酶活性。一旦到达那里,Parkin 就会诱导过氧化物酶体的细胞器选择性自噬,但不会诱导溶酶体的自噬。我们提出,PINK1 与 TOM 复合物的结合允许 PINK1 快速重入,从而使重新极化的线粒体免受自噬的影响,同时排除了线粒体特异性因素对 Parkin 易位和激活的影响。

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