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

The mitochondrial unfolded protein response (UPR) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In , the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPR 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, FSHR-1, in promoting UPR activation. Genetic deficiency of severely attenuates UPR activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPR activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPR, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell nonautonomously in neurons to activate UPR upstream of SPHK-1 signaling in the intestine.