“Todo Nahin, Jodo”- Story of mitochondrial fusion in neural stem cell development

All biological systems ranging from unicellular to multicellular organisms require energy to perform different activities such as cell division, movement, reproduction etc. In eukaryotic cells, this biochemical energy is in the form of adenosine triphosphate (ATP) which is produced by small organelles called mitochondria. Hence mitochondria are considered as a powerhouse or cellular batteries of the cell. In the past few years, mitochondria received considerable attention due to its involvement in other important cellular processes and various diseases. These are highly dynamic, double membranous organelles and continuously undergo cycles of fusion and division depending on cell type, cell cycle stage and demand of the cell. Cells are high on ATP when fused mitochondria happens and low when fragmented. There is dedicated protein machinery involved in the regulation of mitochondrial shape transition and mutation in these causes several diseases like optic atrophy, Parkinson’s disease etc. During Ph.D., I decided to decode the function of mitochondrial dynamics proteins in neural stem cell development using the developing brain of Drosophila melanogaster a.k.a. fruit fly as a model system. A brain is particularly heavily dependent on mitochondria for energy requirement and particularly susceptible to mitochondrial dysfunction. Defects in the mitochondrial function cause several neurodegenerative disorders. Neural stem cells (NSCs) are specialized cells with high proliferative capacity present in the brain. They are responsible for the production of functional cells of the brain such as neurons and glia. Since there is less information available on such an important aspect of brain function, we decided to take up the work and it became the main focus of my Ph.D program: working on Drosophila NSCs to decode the importance of mitochondrial role in stem cell maintenance. 

About 70% of human disease related genes are similar (homologs) to Drosophila and hence many researchers and scientists use this fruit fly for their experimental work. Initial plan of our study was to manipulate the process of fusion (synthesis) and fission (fragmentation) proteins and then examine their effect on NSCs proliferation and differentiation. In cells, genetic information flows from DNA → RNA → Protein. After the protein is synthesized, it carries out different functions in the cell. In our study, these Proteins of interest were proteins involved in mitochondrial dynamics regulation. We downregulated mitochondrial dynamics proteins in NSCs of the Drosophila larval brain. Next, we assessed the effect of these manipulations on NSC growth, differentiation, cell death and energy status of NSCs. We found that inhibition of mitochondrial fusion in NSCs caused production of fewer neurons compared to control NSCs. When fusion was restored, neuronal populations were rescued which confirmed that mitochondrial fusion is essential for the NSC development. This study has shown that unlike many other stem cell types, NSC development is dependent on the fused state of mitochondria. For more details, please go through my research article published in the PLoS Genetics.