Invadolysin, a conserved lipid droplet-associated metalloprotease, is required for mitochondrial function in Drosophila

Mitochondria are the main font of ATP, the principal energy source of the cell, and ROS (Reactive Oxygen Species), important signaling molecules. Mitochondrial morphogenesis and function depend on a hierarchical network of mechanisms in which proteases appear to be center stage. The invadolysin gene encodes an essential, conserved metalloprotease of the M8 family that is necessary for mitosis and cell migration during Drosophila development. We additionally demonstrated that invadolysin is found associated with lipid droplets in cells. Herein we present data demonstrating that invadolysin interacts physically with three mitochondrial ATP synthase subunits. Our studies have focused on the genetic phenotypes of invadolysin and bellwether, the Drosophila homologue of ATP synthase α, mutants. The invadolysin mutation presents defects in mitochondrial physiology similar to what is observed in bellwether mutants. The invadolysin and bellwether mutants have parallel phenotypes that affect lipid storage and mitochondrial electron transport chain activity, which result in a reduction in ATP and an accumulation of ROS. As a consequence, invadolysin larvae show lower energetic status and higher oxidative stress. Our data demonstrate an essential role for invadolysin in mitochondrial function that is crucial for normal development and survival.