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 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling 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. Notably, 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 signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.

在神经退行性疾病中经常观察到线粒体质量控制失败。通过稳定 PTEN 诱导激酶 1 (PINK1) 来检测受损线粒体需要通过将Pink1信使 RNA (mRNA) 束缚在线粒体表面来进行运输。在此，我们报告通过激活胰岛素信号级联来抑制 AMP 激活蛋白激酶 (AMPK)，从而阻止Pink1 mRNA 与线粒体结合。从机制上讲，AMPK 磷酸化其 PDZ 结构域内的 RNA 锚定复合物亚基 SYNJ2BP，这是与 RNA 结合蛋白 SYNJ2 相互作用所必需的磷酸化位点。值得注意的是，添加胰岛素后线粒体Pink1 mRNA 关联的丧失是 PINK1 蛋白激活及其在线粒体自噬途径中作为泛素激酶的功能所必需的，从而将 PINK1 功能置于代谢控制之下。关键遗传阿尔茨海默病危险因子载脂蛋白 E4 在体外诱导胰岛素抵抗，将Pink1 mRNA 保留在线粒体中，并阻止正常的 PINK1 活性，尤其是在神经突中。因此，我们的结果确定了一个通过神经元中胰岛素和 AMPK 信号传导控制Pink1 mRNA 定位和 PINK1 活性的代谢开关，并提出了胰岛素抵抗和线粒体功能障碍之间的机制联系。