A neuro-intestinal circuit controls mitochondrial dynamics and stress resistance

Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. Specific neuropeptidergic signals coordinate the systemic mitochondrial stress response (UPRmt), but whether chemical neurotransmitters also influence this process is unclear. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPRmt in the Caenorhabditis elegans intestine. GABA controls the UPRmt by regulating extra-synaptic ACh release through metabotropic GABAB receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPRmt through ACR-11, an intestinal nicotinic 7 receptor. This neuro-intestinal circuit is critical for nonautonomously regulating mitochondrial dynamics and 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. One-Sentence SummaryRegulation of mitochondrial health with neurotransmission.