PT - JOURNAL ARTICLE AU - Simon Haeussler AU - Assa Yeroslaviz AU - Stéphane G. Rolland AU - Sebastian Luehr AU - Barbara Conradt TI - Genome-wide RNAi screen for regulators of UPR<sup>mt</sup> in <em>Caenorhabditis elegans</em> mutants with defects in mitochondrial fusion AID - 10.1101/2020.07.31.230441 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.07.31.230441 4099 - http://biorxiv.org/content/early/2020/08/01/2020.07.31.230441.short 4100 - http://biorxiv.org/content/early/2020/08/01/2020.07.31.230441.full AB - The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin. We find that approximately 90% of the 299 suppressors and 86 enhancers identified are conserved in humans and that one third of the conserved genes have been implicated in human disease. Furthermore, many of the 385 genes have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. In addition, we find that enhancers are predominantly ‘mitochondrial’ genes and suppressors ‘non-mitochondrial’ genes, which indicates that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function that when disrupted can be compensated for by a variety of cellular processes. Our analysis of ‘non-mitochondrial’ enhancers and ‘mitochondrial’ suppressors suggests that organellar contact sites, especially between ER and mitochondria, are of importance for mitochondrial homeostasis. Finally, we uncovered several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants, found a potential link between pre-mRNA splicing and UPRmt activation and identified the Miga-1/2 ortholog K01D12.6 as required for mitochondrial dynamics in C. elegans.