The role of mitochondrial dynamics and metabolism in neuroblast differentiation in Drosophila melanogaster

Abstract

Mitochondria regulate various cellular processes such as the production of ATP, generation of ROS, calcium buffering and apoptosis. The mitochondrial network is actively remodeled through cycles of fusion and fission, and mitochondrial defects are associated with diseases. It is clear that mitochondrial functions in differentiated tissues are highly regulated; however, their role in cell differentiation is not extensively studied. We focussed on Drosophila neural stem cells, called neuroblasts, to analyze mitochondrial functions during cell differentiation using a genetics approach. We examined the differentiation of type-II neuroblasts after perturbing mitochondrial dynamics and metabolism by targeting mitochondrial fusion proteins Opa1 and Marf, fission protein Drp1, and Complex-IV of the electron transport chain, allowing for the elucidation of the role of mitochondrial functions in neuroblast differentiation. Tissue-specific depletion of Opa1 reduced mitochondrial fusion in neuroblasts with a concomitant decrease in the number of differentiated progeny produced by the neuroblasts. Additionally, inhibition of mitochondrial fusion resulted in reduced Notch signaling, increased cytochrome-c and reactive oxygen species in the type-II neuroblasts. In comparison, we observed hyper-fused mitochondria in Drp1 mutants, which surprisingly had no effect on neuroblast differentiation. Further, suppression of the activity of the electron transport chain by depletion of mitochondrial Complex-IV also decreased neuroblast differentiation. We thus hypothesize that fused mitochondria are a prerequisite in neuroblasts for sustaining proper signaling activity. Our studies have also revealed cross-talk between Notch signaling and mitochondrial dynamics - Notch signaling maintains fused mitochondria in type-II neuroblasts possibly by regulating the expression of mitochondrial fusion genes; and fragmented mitochondria hinder Notch signaling, subsequently inhibiting the production of differentiated cells.