Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, U.K.
Wellcome Centre for Mitochondrial Research, Newcastle University, Tyne NE2 4HH, U.K.
J Med Chem. 2023 Jun 8;66(11):7645-7656. doi: 10.1021/acs.jmedchem.3c00555. Epub 2023 May 29.
Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that -substituted adenosines, such as -(2-furanylmethyl)adenosine (known as kinetin riboside) and -benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts. Interestingly, pre-treatment of HeLa cells and astrocytes with these compounds inhibited elevated ubiquitin phosphorylation that is induced by established mitochondrial depolarizing agents, carbonyl cyanide -chlorophenyl-hydrazine and niclosamide. Together, this highlights -substituted adenosines as progenitor PINK1 activators that could potentially be developed, in the future, as treatments for aged and sporadic PD patients who have elevated phosphorylated ubiquitin levels in the brain.
线粒体蛋白激酶 PTEN 诱导激酶 1（PINK1）在线粒体去极化时对泛素进行磷酸化，是通过线粒体自噬回收受损线粒体的重要中间步骤。由于 PINK1 突变可导致早发性帕金森病（PD），因此人们越来越关注 PINK1 介导线粒体自噬的小分子激活剂作为潜在的 PD 治疗方法。在此，我们发现 -取代腺苷，如 -（2-呋喃甲基）腺苷（又称激动素核苷）和 -苄基腺苷，可在 HeLa 细胞中激活 PINK1，并在原代小鼠成纤维细胞中诱导 PINK1 依赖性线粒体自噬。有趣的是，这些化合物预处理 HeLa 细胞和星形胶质细胞可抑制由已建立的线粒体去极化剂，羰基氰化物 -氯苯腙和尼可刹米诱导的泛素磷酸化升高。总之，这突显了 -取代腺苷作为前体 PINK1 激活剂的潜力，未来可能会开发出针对具有大脑中升高的磷酸化泛素水平的老年和散发性 PD 患者的治疗方法。
