FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans

The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In Caenorhabditis elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues are not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein-coupled receptor, , in promoting UPRmt activation. Genetic deficiency of severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. functions in a common genetic pathway with /sphingosine kinase to promote UPRmt activation, and regulates the mitochondrial association of in the intestine. Through tissue-specific rescue assays, we show that functions in neurons to activate the UPRmt, to promote mitochondrial association of in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that functions cell nonautonomously in neurons to activate UPRmt upstream of signaling in the intestine.