Mechanism Of Drp1Rescue PINK1Null Mutant Phenotypes In Drosophila

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. One of the most important pathogenic mechanism of PD is mitochondrial dysfunction. Over the last decades,16genes mediating familial forms of PD have been identified, includingPTEN-induced putative kinase1(PINK1; PARK6) that its mutations cause autosomal-recessive Parkinson’s disease. PINK1, a Ser/Thr kinases anchored on mitochondrial, plays essential roles in maintaining mitochondrial structures and function. PINK1null mutant flies show movement defects and mitochondrial structural and functional abnormalities. Normal mitochondria go through continuous fusion and fission. Disruption of this process leads to abnormalities of mitochondrial structure and function, and eventually causes cell damage. Drpl is a mitochondrial fission related protein. Genetic manipulations that promote mitochondrial fission by overexpression of Drp1suppress DrosophilaPINKl null mutant phenotypes. However, the specific mechanism remains unclear. Our previous study found phosphorylation of Ser596in Drp1changes in PINK1knockout mice. Here we explore the effect of Drp1S596phosphorylation on PINK1null mutant flies.Objective:Exploring the effect of Drp1S596phosphorylation on PINK1null mutant flies.Methods:We overexpressed Drp1WT, Drp1S596A (mimic dephosphorylation) and Drp1S596D (mimic phosphorylation) in Drosophila with PINK1null mutation background to observe impacts of Drp1S596phosphorylation on the abnormal phenotype caused by PINK1deficit.Results:Both Drp1S596D and Drp1WT could rescue PINK1deficit related abnormal phenotypes in Drosophila, including wings abnormal posture, collapsed thorax, locomotive defects, decreased ATP synthesis, as well as abnormal mitochondrial morphology in muscle and dopaminergic neurons. On the other hand, Drp1S596A could not rescue abnormal mitochondrial morphology in muscle and dopaminergic neurons in PINK1deficit flies, but did rescue the wings abnormality and ATP synthesis.Conclusion:Drp1phosphorylation differentially regulates PINK1mediated mitochondrial morphology and function. This study illustrate the mechanism in which Drp1rescues PINK1null mutant phenotype, and provide evidence for further understanding of the pathogenesis of PD.