<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "A mitochondrial PERK mediates mitonuclear communication through induction of an ATF4-dependent transcriptional response"^^ . "Intracellular homeostasis depends on a multitude of enzymatic networks that control all\r\nbasic cellular processes. To respond to stress – in the sense of disturbed homeostasis – cells\r\nhave evolved adaptive responses, many of which involve nuclear transcription of proteins\r\nintended to counteract the stress and re-establish homeostasis. A particular stress, known to\r\ninduce transcriptional responses, is protein aggregation or misfolding. Different, specific\r\nresponses have been well characterised in response to protein folding stress within the\r\ncytosol or the endoplasmic reticulum. Protein folding stress within mitochondria has also\r\nbeen described to induce a nuclear transcriptional response. However, how folding stress\r\nwithin mitochondria is sensed and signalled to the nucleus, through mitonuclear\r\ncommunication or mitochondrial retrograde signalling, remains poorly understood.\r\nUsing a population of progenitor cells residing in the larval eye-imaginal disc of\r\nDrosophila melanogaster, this thesis demonstrates that the eIF2α-kinase PERK and its\r\ndownstream target ATF4 mediate mitonuclear communication in response to disturbed\r\nprotein handling within mitochondria.\r\nPERK has been widely recognised as a sensor of protein folding within the lumen of the\r\nendoplasmic reticulum. Activation of PERK triggers a response called Integrated Stress\r\nResponse (ISR) that attenuates translation rates, which in turn induces ATF4 to transcribe\r\ngenes with cytoprotective function. This work now shows that the Drosophila genome\r\nencodes a PERK isoform that is targeted for mitochondrial import and fulfils a similar function\r\nin this organelle. The transcriptional response through ATF4 confirmed known ISR target\r\ngenes and additionally showed that Drosophila ATF4 functions as an inducer of the\r\nmitochondrial Unfolded Protein Response (UPRmt) as well. A comparison with mitonuclear\r\nsignalling in other model organisms argues for substantial rewiring of the response during\r\nevolution, though most proteins originated at the base of metazoa.\r\nThis thesis utilised Drosophila imaginal disc progenitor cells that build the adult eye.\r\nDuring development of the tissue, the PERK-ATF4 response protects fitness of cells with\r\ndefects in the mitochondrial electron transport chain (ETC). Intriguingly, this adaptation can\r\nbe hi-jacked by growth-promoting signalling pathways to enhance their oncogenic potential.\r\nIn conclusion, this thesis defines a molecular signalling pathway activated by ETC defects\r\nand links the pathway to in vivo phenotypes."^^ . "2018" . . . . . . . "Sebastian"^^ . "Sorge"^^ . "Sebastian Sorge"^^ . . . . . . "A mitochondrial PERK mediates mitonuclear communication through induction of an ATF4-dependent transcriptional response (PDF)"^^ . . . "Thesis_SebastianSorge.pdf"^^ . . . "A mitochondrial PERK mediates mitonuclear communication through induction of an ATF4-dependent transcriptional response (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #25507 \n\nA mitochondrial PERK mediates mitonuclear communication through induction of an ATF4-dependent transcriptional response\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .