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Animals integrate environmental and internal cues to maintain homeostasis and health. The mitochondrial stress response is an essential cytoprotective mechanism, and priming its activation provides a survival advantage. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signalling from carbon dioxide sensing neurons to govern a non-canonical mitochondrial stress response in the intestine. This stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. GCY-9 loss disrupts pathogen avoidance, leading to indiscriminate feeding. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset risks associated with this behaviour. Thus, environmental sensing by peripheral neurons can pre-emptively enhance systemic mitochondrial function in response to metabolic uncertainty. One-Sentence Summary Protecting mitochondria by integrating environmental signals ### Competing Interest Statement The authors have declared no competing interest. National Health and Medical Research Council, GNT1137645, GNT2000766

The exploration of the cell biological aspects of nervous system development, function and health continues delivering groundbreaking pieces of information that push forward our understanding of brai…