Interaction of mitochondrial fusion and electron transport chain function in differentiation of Drosophila neural stem cells

Abstract

Mitochondrial fusion and fission, along with the activity of the electron transport chain in neural stem cells (NSCs), play an essential role in regulating the metabolic demands of differentiation. However, the mechanisms by which mitochondrial morphology and activity together regulate NSC differentiation are poorly understood. This study explored the interaction between mitochondrial morphology and electron transport chain complexes in vivo in Drosophila NSC (neuroblast) differentiation. We found that the inhibition of oxidative phosphorylation by depleting different subunits of complex I, II, IV and V did not affect the number of type II neuroblasts in the brain but reduced the number of intermediate precursor cells, ganglion mother cells and neurons in the type II neuroblast lineage. This differentiation defect was suppressed by forced mitochondrial fusion on additional depletion of Drp1 in complex I and IV-depleted neuroblasts but not in complex II and V-deficient neuroblasts. We further explored the mechanism by which ETC complex depletion affects differentiation and fusion rescue. We found that the depletion of complex I subunits led to a decrease in mitochondrial membrane potential, an increase in ROS, a decline in nuclear cyclin E, and a decrease in the proliferation of the neuroblasts and mature intermediate precursor cells. In addition to forced mitochondrial fusion, these defects were reversed by overexpression of ROS-scavenging enzymes such as SOD2 and catalase in the neuroblast. Together, this study reveals the role of mitochondrial morphology in regulating mitochondrial activity to control the levels of ROS for proper differentiation in the type II neuroblast lineage.