Abstract
AbstractLoss of function mutations of the PINK1 kinase cause familial early-onset Parkinson’s disease. PINK1 is activated upon mitochondrial damage to phosphorylate Ubiquitin and Parkin to trigger removal of damaged mitochondria by autophagy (mitophagy). PINK1 also indirectly phosphorylates a subset of Rab GTPases including Rab8A. We have performed a siRNA screen of all human Ser/Thr kinases in HeLa cells and discovered the integrated stress response kinase EIF2AK1 (HRI) negatively regulates PINK1 following mitochondrial damage. We demonstrate that EIF2AK1 knockout cells enhance mitochondrial depolarization-induced stabilization of PINK1 and increased phosphorylation of Ubiquitin and Rab8A. We confirm our findings in multiple human cell lines including SK-OV-3, U2OS and ARPE-19 cells. Knockdown of upstream components of the recently described mitochondrial-cytosol relay pathway, OMA1 and DELE1, enhanced PINK1 stabilisation and activation similar to EIF2AK1. Using themito-QC mitophagy reporter in human cells, we observe that EIF2AK1 knockdown moderately increases PINK1-dependent mitophagy. Our findings indicate that EIF2AK1 is a negative regulator of PINK1 and suggest that inhibitors of EIF2AK1 could have therapeutic benefits in Parkinson’s disease and related disorders of ageing and mitophagy.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献