Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans.

Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPR) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPR in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPR in the Caenorhabditis elegans intestine. GABA controls the UPR by regulating extra-synaptic ACh release through metabotropic GABA receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPR through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses.