Abstract

The overall goal of our work is to understand the effects of mitochondrial dysfunction in the nervous system and how this contributes to neurodegeneration. Mitochondria are abundant in almost every cell type and are particularly important in the nervous system. Mitochondria generate the majority of cellular ATP but also metabolize fatty acids, synthesize amino acids, buffer cellular calcium ions, produce reactive oxygen species, synthesise iron-sulphur clusters and mediate programmed cell death. Altered mitochondrial activity or mitochondrial dysfunction causes ‘mitochondrial retrograde signalling’ pathways to be activated, resulting in altered nuclear gene expression. To study mitochondrial retrograde signalling in the nervous system we have developed Drosophila models of neuronal specific mitochondrial dysfunction. I will discuss our recent work where we have shown that mitochondrial dysfunction activates endoplasmic reticulum stress signalling in neurons. We have furthermore used transcriptomics and metabolomics to identify a novel mechanism, triggered by mitochondrial dysfunction and endoplasmic reticulum stress signalling, which contributes to loss of neuronal function in Drosophila. This mechanism may be relevant to mitochondrial disease and neurodegenerative diseases associated with mitochondrial dysfunction.