Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans

Mitochondrial perturbations within neurons communicate stress signals to peripheral tissues, coordinating
organismal-wide mitochondrial homeostasis for optimal fitness. However, the neuronal control of the systemic stress regulation remains poorly understood. Here, we identified a G-protein-coupled receptor
(GPCR), SRZ-75, that couples with Gaq signaling in a pair of chemosensory ADL neurons to drive the mitochondrial unfolded protein response (UPRmt) activation in the intestine via the release of neuropeptides in
Caenorhabditis elegans. Constitutive activation of Gaq signaling in the ADL neurons is sufficient to induce
the intestinal UPRmt, leading to increased stress resistance and metabolic adaptations. Ablation of ADL neurons attenuates the intestinal UPRmt activation in response to various forms of neuronal mitochondrial
dysfunction. Thus, GPCR and its Gaq downstream signaling in two sensory neurons coordinate the systemic
UPRmt activation, representing a previously uncharacterized, but potentially conserved, neuronal signaling
for organismal-wide mitochondrial stress regulation.