Atg1-mediated autophagy suppresses tissue degeneration in<i>pink1/parkin</i>mutants by promoting mitochondrial fission in<i>Drosophila</i>

Abstract

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