Abstract
Mitochondria dysfunction is considered as a hallmark of multiple neuro-degenerative diseases, including Parkinson's disease (PD). PD familial genes, Pink1 and parkin function in a conserved pathway that regulates mitochondrial function including dynamics (fusion and fission). Mammalian cell culture studies suggested that pink1/ parkin pathway promotes mitophagy (mitochondrial autophagy). Mitophagy through mitochondrial fission and auto-lysosomal recycling was considered as a quality control system in organelle level. Whether this quality control machinery involves in PD pathogenesis in vivo, remains elusive. Here, we found elevating autophagy by Atg1 over-expression can significantly rescue mitochondrial defects and apoptotic cell death in pink1 and parkin mutants in Drosophila. Surprisingly, the rescue effect relied both on the autophagy-lysosome machinery and on drp1, a mitochondrial fission molecule. We further showed that Atg1 promotes mitochondrial fission by post-transcriptional increasing of Drp1 protein level. In contrast, increasing fission (by drp1 overexpression) or inhibiting fusion (by mfn knocking down) rescue pink1 mutants when lysosomal or proteasomal machinery were impaired. Taken together, our results identified atg1 as a dual function node to control mitochondrial quality by promoting mitochondria fission and autophagy, which makes it a potential therapeutic target for treatment of mitochondrial dysfunction related diseases, including PD.
