Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.
Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.
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DOI：
10.1083/jcb.201708191
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发表时间：
2018-04-02
期刊：
影响因子：
--
通讯作者：
Behrens J
中科院分区：
文献类型：
--
作者：
Bernkopf DB;Jalal K;Brückner M;Knaup KX;Gentzel M;Schambony A;Behrens J
线粒体应激诱导PARL介导的线粒体磷酸酶Pgam 5的裂解和胞质释放。在胞质溶胶中，Pgam 5与Wnt途径组分轴蛋白相互作用并使轴蛋白结合的β-连环蛋白去磷酸化，从而细胞固有地激活Wnt/β-连环蛋白信号传导以诱导线粒体生物发生。线粒体丰度是动态调节的，并且先前显示通过Wnt/β-连环蛋白信号传导增加。Pgam 5是一种线粒体磷酸酶，其被菱形蛋白酶早老蛋白相关的菱形样蛋白（PARL）切割，并在线粒体应激后从膜释放。在这项研究中，我们发现Pgam 5与细胞质中的Wnt通路组分轴蛋白相互作用，阻断轴蛋白介导的β-catenin降解，并增加β-catenin水平和β-catenin依赖性转录。Pgam 5通过诱导β-catenin去磷酸化来稳定β-catenin，这是一种依赖于轴突的方式。由羰基氰化物间氯苯腙（CCCP）处理引发的线粒体应激导致内源性Pgam 5的胞质释放和随后的β-连环蛋白的去磷酸化，其在Pgam 5和PARL敲除细胞中强烈减少。类似地，缺氧应激产生胞质Pgam 5并导致β-连环蛋白的稳定，其被Pgam 5敲除所消除。稳定表达胞质Pgam 5的细胞表现出升高的β-连环蛋白水平和增加的线粒体数量。我们的研究揭示了一种新的机制，通过这种机制，受损的线粒体可能通过Pgam 5-β-catenin轴细胞内在激活Wnt信号来诱导线粒体库的补充。
Mitochondrial stress induces PARL-mediated cleavage and cytosolic release of the mitochondrial phosphatase Pgam5. In the cytosol, Pgam5 interacts with the Wnt pathway component axin and dephosphorylates axin-bound β-catenin, thereby cell-intrinsically activating Wnt/β-catenin signaling to induce mitochondrial biogenesis. Mitochondrial abundance is dynamically regulated and was previously shown to be increased by Wnt/β-catenin signaling. Pgam5 is a mitochondrial phosphatase which is cleaved by the rhomboid protease presenilin-associated rhomboid-like protein (PARL) and released from membranes after mitochondrial stress. In this study, we show that Pgam5 interacts with the Wnt pathway component axin in the cytosol, blocks axin-mediated β-catenin degradation, and increases β-catenin levels and β-catenin–dependent transcription. Pgam5 stabilized β-catenin by inducing its dephosphorylation in an axin-dependent manner. Mitochondrial stress triggered by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment led to cytosolic release of endogenous Pgam5 and subsequent dephosphorylation of β-catenin, which was strongly diminished in Pgam5 and PARL knockout cells. Similarly, hypoxic stress generated cytosolic Pgam5 and led to stabilization of β-catenin, which was abolished by Pgam5 knockout. Cells stably expressing cytosolic Pgam5 exhibit elevated β-catenin levels and increased mitochondrial numbers. Our study reveals a novel mechanism by which damaged mitochondria might induce replenishment of the mitochondrial pool by cell-intrinsic activation of Wnt signaling via the Pgam5–β-catenin axis.
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