Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response (UPR) 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 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 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. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress response in the nervous system.