Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response (UPR^mt) and the cell non-autonomous modulation of longevity. However, the mechanism by which the nervous system senses mitochondrial stress and communicates to the distal tissues to induce UPR^mt remains unclear. Here we employ the tissue-specific CRISPR-Cas9 approach to disrupt mitochondrial function only in the nervous system of Caenorhabditis elegans, and reveal a cell non-autonomous induction of UPR^mt in peripheral cells. We further show that a neural sub-circuit composed of three types of sensory neurons, and one interneuron is required for sensing and transducing neuronal mitochondrial stress. In addition, neuropeptide FLP-2 functions in this neural sub-circuit to signal the non-autonomous UPR^mt. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress response in the nervous system.