%0 Generic
%A Sorge, Sebastian
%D 2018
%F heidok:25507
%K PERK  ATF4  UPR
%R 10.11588/heidok.00025507
%T A mitochondrial PERK mediates mitonuclear communication through induction of an ATF4-dependent transcriptional response
%U https://archiv.ub.uni-heidelberg.de/volltextserver/25507/
%X 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.