School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
EMBO J. 2018 Nov 2;37(21). doi: 10.15252/embj.201798899. Epub 2018 Sep 20.
PGAM5, a mitochondrial protein phosphatase that is genetically and biochemically linked to PINK1, facilitates mitochondrial division by dephosphorylating the mitochondrial fission factor Drp1. At the onset of mitophagy, PGAM5 is cleaved by PARL, a rhomboid protease that degrades PINK1 in healthy cells, and the cleaved form facilitates the engulfment of damaged mitochondria by autophagosomes by dephosphorylating the mitophagy receptor FUNDC1. Here, we show that the function and localization of PGAM5 are regulated by syntaxin 17 (Stx17), a mitochondria-associated membrane/mitochondria protein implicated in mitochondrial dynamics in fed cells and autophagy in starved cells. In healthy cells, loss of Stx17 causes PGAM5 aggregation within mitochondria and thereby failure of the dephosphorylation of Drp1, leading to mitochondrial elongation. In Parkin-mediated mitophagy, Stx17 is prerequisite for PGAM5 to interact with FUNDC1. Our results reveal that the Stx17-PGAM5 axis plays pivotal roles in mitochondrial division and PINK1/Parkin-mediated mitophagy.
PGAM5 是一种线粒体蛋白磷酸酶，它在遗传和生化上与 PINK1 相关，通过去磷酸化线粒体分裂因子 Drp1 来促进线粒体分裂。在自噬开始时，PARL（一种菱形蛋白酶）会切割 PGAM5，PARL 在健康细胞中降解 PINK1，而切割后的形式通过去磷酸化自噬受体 FUNDC1 来促进受损线粒体被自噬体吞噬。在这里，我们表明 PGAM5 的功能和定位受突触融合蛋白 17（Stx17）的调节，Stx17 是一种与线粒体相关的膜/线粒体蛋白，在进食细胞中的线粒体动力学和饥饿细胞中的自噬中起作用。在健康细胞中，Stx17 的缺失会导致 PGAM5 在线粒体中聚集，从而无法去磷酸化 Drp1，导致线粒体伸长。在 Parkin 介导的自噬中，Stx17 是 PGAM5 与 FUNDC1 相互作用的前提。我们的结果表明，Stx17-PGAM5 轴在线粒体分裂和 PINK1/Parkin 介导的自噬中起着关键作用。
