Insulin signaling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons

Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 mRNA by tethering it to the mitochondrial surface. Here, we report that inhibition of AMPK by activation of the insulin signaling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Interestingly, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin-resistance in vitro by the key genetic Alzheimer-risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signaling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.

神经退行性疾病中常可观察到线粒体质量控制（mitochondrial quality control）功能异常。PTEN诱导激酶1（PTEN-induced kinase 1, PINK1）识别受损线粒体，依赖于将Pink1 mRNA锚定至线粒体表面进行转运。本研究发现，通过激活胰岛素信号级联抑制腺苷酸活化蛋白激酶（AMPK），可阻止Pink1 mRNA与线粒体结合。从机制上看，AMPK可在PDZ结构域内对RNA锚定复合物亚基SYNJ2BP进行磷酸化，该磷酸化位点是其与RNA结合蛋白SYNJ2相互作用的必要条件。有趣的是，胰岛素处理后线粒体与Pink1 mRNA的结合丧失，这对于PINK1蛋白的激活及其在线粒体自噬通路中作为泛素激酶的功能是必需的，从而使PINK1的功能受到代谢调控。利用阿尔茨海默病关键遗传风险因子载脂蛋白E4（apolipoprotein E4）在体外诱导胰岛素抵抗，可使Pink1 mRNA滞留于线粒体表面，并损害PINK1的正常活性，尤其在神经元突起中。综上，本研究揭示了一条通过神经元内胰岛素与AMPK信号通路调控Pink1 mRNA定位及PINK1活性的代谢开关，并提出了胰岛素抵抗与线粒体功能异常之间的潜在机制关联。