Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans, 2024, Cornell+

[SNT Gatchaman]

Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans
Cornell, Rebecca; Cao, Wei; Harradine, Bernie; Godini, Rasoul; Handley, Ava; Pocock, Roger

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 UPR mt in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPR mt in the Caenorhabditis elegans intestine. GABA controls the UPR mt by regulating extrasynaptic ACh release through metabotropic GABA B receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh degradative enzymes induce the UPR mt 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.

Link | PDF (Nature Communications) [Open Access]

 

[SNT Gatchaman]

In worms, though however —

In vertebrates, nicotinic α7 receptors can act in the liver (some functions of which are performed by the C. elegans intestine) to promote cell survival, suggesting that mechanisms we describe here are phylogenetically conserved.

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In summary, we discovered a neuro-intestinal circuit that regulates the UPRmt and organismal survival. By screening animals lacking specific neurotransmitters, we found that balanced GABAergic and cholinergic signalling is essential for non-cell-autonomous UPRmt regulation. We found that GABA released from ventral nerve cord motor neurons controls the UPR mt through two metabotropic GABA B receptor subunits that are expressed on, and inhibit, cholinergic motor neurons. Appropriate control of ACh levels is critical for UPRmt regulation, as animals lacking the ACh-degradative enzymes exhibit a two-fold induction of the UPRmt.

Further, we discovered that UPR mt induction by increased systemic ACh is dependent on ACR-11, an α7 nAChR receptor acting in the intestine. […] In addition to regulating the UPRmt, elevated ACh induces mitochondrial fragmentation and reduces survival of oxidative stress. Interestingly, we found that the ACR11 α7nAChR receptor can act independently to ACh, with animals lacking ACR-11 exhibiting more intestinal mitochondrial fragmentation and autophagy irrespective of ACh levels. These distinctions likely provide animals lacking ACR-11 a survival advantage in oxidative stress conditions.

 

[Midnattsol]

In worms, though —

Worms that can survive with only about 25% of their genetic material (given the environment is supportive enough, ie no need for genes that convert one amino acid to another since all amino acids are provided etc)

 

[Jonathan Edwards]

It might still be relevant.

I still think there is a small possibility that EACh signalling is central to ME/CFS. The Wust pictures may show something odd going on with acetylcholinesterase.