Cell-to-cell communication in the brain and tissue-specific phenotypes of mitochondrial disease (360G-Wellcome-219615_Z_19_Z)

Mitochondria are cellular organelles primarily involved in energy production. They are considered to be key to the function of eukaryotic cells. Nevertheless, mitochondrial diseases often only present in adulthood with tissue-specific symptoms. This means that cells and tissues must have coping strategies which temporarily maintain normal function when confronted with mitochondrial dysfunction. This proposal aims to test the hypothesis that cell-type composition and metabolic interactions between different cell types renders specific tissues more or less vulnerable to mitochondrial dysfunction. The neural stem cell (NSC) niche in the developing Drosophila brain is a powerful in vivo model for the microenvironment of neurons and NSCs in our human brain. I plan to study the in vivo metabolic requirements of Drosophila NSCs (Aim 1), and the metabolic and transcriptional response of surrounding niche cells upon mitochondrial dysfunction (Aim 2). In the last part of my proposal, I will investigate how metabolic regulation of the nuclear genome provide both a nuclear sensing mechanism and a buffer to tissue-wide mitochondrial dysfunction (Aim 3). Elucidating generic mechanisms of the tissue-wide response to mitochondrial dysfunction will lead to better insight into metabolic origins of neurodegenerative diseases and cancer and has the potential to uncover novel therapeutic approaches.