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Abstract

Intracellular homeostasis depends on a multitude of enzymatic networks that control all basic cellular processes. To respond to stress – in the sense of disturbed homeostasis – cells have evolved adaptive responses, many of which involve nuclear transcription of proteins intended to counteract the stress and re-establish homeostasis. A particular stress, known to induce transcriptional responses, is protein aggregation or misfolding. Different, specific responses have been well characterised in response to protein folding stress within the cytosol or the endoplasmic reticulum. Protein folding stress within mitochondria has also been described to induce a nuclear transcriptional response. However, how folding stress within mitochondria is sensed and signalled to the nucleus, through mitonuclear communication or mitochondrial retrograde signalling, remains poorly understood. Using a population of progenitor cells residing in the larval eye-imaginal disc of Drosophila melanogaster, this thesis demonstrates that the eIF2α-kinase PERK and its downstream target ATF4 mediate mitonuclear communication in response to disturbed protein handling within mitochondria. PERK has been widely recognised as a sensor of protein folding within the lumen of the endoplasmic reticulum. Activation of PERK triggers a response called Integrated Stress Response (ISR) that attenuates translation rates, which in turn induces ATF4 to transcribe genes with cytoprotective function. This work now shows that the Drosophila genome encodes a PERK isoform that is targeted for mitochondrial import and fulfils a similar function in this organelle. The transcriptional response through ATF4 confirmed known ISR target genes and additionally showed that Drosophila ATF4 functions as an inducer of the mitochondrial Unfolded Protein Response (UPRmt) as well. A comparison with mitonuclear signalling in other model organisms argues for substantial rewiring of the response during evolution, though most proteins originated at the base of metazoa. This thesis utilised Drosophila imaginal disc progenitor cells that build the adult eye. During development of the tissue, the PERK-ATF4 response protects fitness of cells with defects in the mitochondrial electron transport chain (ETC). Intriguingly, this adaptation can be hi-jacked by growth-promoting signalling pathways to enhance their oncogenic potential. In conclusion, this thesis defines a molecular signalling pathway activated by ETC defects and links the pathway to in vivo phenotypes.