Drosophila phosphatidylinositol-4 kinase fwd promotes mitochondrial fission and can suppress Pink1/parkin phenotypes

Balanced 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 in Drosophila Pink1/parkin mutants. We sought additional factors that impinge on mitochondrial dynamics and which may also suppress Pink1/parkin phenotypes. We found that the Drosophila phosphatidylinositol 4-kinase III beta 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 in fwd mutants, including locomotor deficits and shortened lifespan, which are accompanied by mitochondrial dysfunction. Finally, we found that fwd overexpression can suppress locomotor deficits and mitochondrial disruption in Pink1/parkin mutants, 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 summary Mitochondria are dynamic organelles 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, sustain cell viability. This is critically important in high energy-demanding, post-mitotic tissues such as neurons. We previously identified Drosophila phosphatidylinositol-4 kinase fwd as a pro-fission factor in a cell-based screen. Here we show that loss of fwd regulates mitochondrial fission in vivo, and acts genetically downstream of Drp1. We identified new phenotypes in fwd mutants, similar to loss of Pink1/parkin, two genes linked to Parkinson's disease and key regulators of mitochondrial homeostasis. Importantly, fwd overexpression is able to substantially suppress locomotor and mitochondrial phenotypes in Pink1/parkin mutants, suggesting that manipulating phosphoinositides may represent a route to tackling Parkinson's disease.