Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in <em>Drosophila melanogaster</em>

Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.PINK1与Parkin的突变可引发家族性早发性帕金森病。在黑腹果蝇(Drosophila melanogaster)中，PINK1和Parkin突变体呈现相似的表型特征，包括线粒体肿胀失能、肌肉退行性变、能量耗竭以及多巴胺能(DA)神经元丢失。我们既往研究表明，PINK1与Parkin可与线粒体融合/分裂通路发生遗传互作；近期另有研究提出，PINK1与Parkin可构建一套涉及线粒体自噬的线粒体质量控制系统。然而，目前PINK1/Parkin功能、线粒体分裂/融合与自噬三者之间的体内关联仍未明确，PINK1致病过程中其他关键细胞事件亦有待探明。本研究证实，PINK1可与蛋白质翻译通路发生遗传互作：通过激活S6K增强翻译水平，会显著加重PINK1突变体的表型；而降低翻译水平则可缓解该表型。通过过表达Atg1(自噬相关基因1)诱导自噬，同样可挽救PINK1突变体的表型，即使在S6K激活的条件下亦是如此。PINK1突变体中本身已存在翻译水平下调与自噬激活的现象，提示这二者是对PINK1失活所致线粒体功能障碍的代偿性细胞应答，其作用推测为维持能量稳态。值得注意的是，在S6K激活的情况下出现的PINK1突变体表型加重，可通过Parkin完全挽救，且这一过程似乎不依赖自噬途径。本研究结果揭示了细胞对PINK1失活的复杂应答机制，并提出通过调控代偿性应答以开发新型治疗策略的新思路。