Drosophilaphosphatidylinositol-4 kinasefwdpromotes mitochondrial fission and can suppressPink1/parkinphenotypes

AbstractBalanced mitochondrial fission and fusion play an important role in shaping and distributing mitochondria, as well as contributing to mitochondrial homeostasis and adaptation to stress. In particular, mitochondrial fission is required to facilitate degradation of damaged or dysfunctional units via mitophagy. Two Parkinson’s disease factors, PINK1 and Parkin, are considered key mediators of damage-induced mitophagy, and promoting mitochondrial fission is sufficient to suppress the pathological phenotypes inPink1/parkinmutantDrosophila. We sought additional factors that impinge on mitochondrial dynamics and which may also suppressPink1/parkinphenotypes. We found that theDrosophilaphosphatidylinositol 4-kinase IIIβ homologue, Four wheel drive (Fwd), promotes mitochondrial fission downstream of the pro-fission factor Drp1. Previously described only as male sterile, we identified several new phenotypes infwdmutants, including locomotor deficits and shortened lifespan, which are accompanied by mitochondrial dysfunction. Finally, we found thatfwdoverexpression can suppress locomotor deficits and mitochondrial disruption inPink1/parkinmutants, consistent with its function in promoting mitochondrial fission. Together these results shed light on the complex mechanisms of mitochondrial fission and further underscore the potential of modulating mitochondrial fission/fusion dynamics in the context of neurodegeneration.Author SummaryMitochondria are dynamic oganelles that can fuse and divide, in part to facilitate turnover of damaged components. These processes are essential to maintain a healthy mitochondrial network, and, in turn, maintain cell viability. This is critically important in high-energy, post-mitotic tissues such as neurons. We previously identifiedDrosophilaphosphatidylinositol-4 kinasefwdas a pro-fission factor in a cell-based screen. Here we show that loss offwdregulates mitochondrial fissionin vivo, and acts genetically downstream ofDrp1. We identified new phenotypes infwdmutants, similar to loss ofPink1/parkin, two genes linked to Parkinson’s disease and key regulators of mitochondrial homeostasis. Importantly,fwdoverexpression is able to substantially suppress locomotor and mitochondrial phenotypes inPink1/parkinmutants, suggesting manipulating phophoinositides may represent a novel route to tackling Parkinson’s disease.