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

Nat Commun. 2024 Aug 3;15(1):6594. doi: 10.1038/s41467-024-50973-y.

Abstract

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 (UPRmt) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPRmt in physiological conditions is not well understood. 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 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.

MeSH terms

  • Acetylcholine* / metabolism
  • Animals
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Caenorhabditis elegans* / genetics
  • Caenorhabditis elegans* / metabolism
  • Caenorhabditis elegans* / physiology
  • Intestines / physiology
  • Mitochondria* / metabolism
  • Neurons / metabolism
  • Oxidative Stress
  • Receptors, GABA-B / genetics
  • Receptors, GABA-B / metabolism
  • Signal Transduction*
  • Stress, Physiological
  • Synaptic Transmission / physiology
  • Unfolded Protein Response
  • alpha7 Nicotinic Acetylcholine Receptor / genetics
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Acetylcholine
  • alpha7 Nicotinic Acetylcholine Receptor
  • Caenorhabditis elegans Proteins
  • gamma-Aminobutyric Acid
  • Receptors, GABA-B