Abstract:Mitochondria play a pivotal role in the generation of signals coupling metabolism with neurotransmitter release, but a role for mitochondrial-produced ROS in regulating neurosecretion has not been described. Here we show that endogenously produced hydrogen peroxide originating from axonal mitochondria (mtH2O2) functions as a signaling cue to selectively regulate the secretion of a FMRFamide-related neuropeptide (FLP-1) from a pair of interneurons (AIY) in C. elegans. We show that pharmacological or genetic man… Show more
“…The interneurons SMBD and SMDD were inconsistently labeled by flp-1 p(1.5 kb)::Cre and flp-1 p(513 bp)::Cre. GFP reporters made with flp - 1 p(1.5 kb) or flp-1 p(513 bp) were only expressed in AVK in larval and adult stages as shown in Figures 3C and S3C , and also shown by others (Jia and Sieburth, 2021; Li et al, 1999; Oranth et al, 2018).…”
Pathogenic infection elicits sickness behaviors that promote recovery and survival of the host. For example, following infection with the pathogenic bacterium Pseudomonas aeruginosa PA14, the nematode Caenorhabditis elegans modifies its sensory preferences to avoid the pathogen. Here we identify antagonistic neuromodulatory circuits that shape this sickness behavior. Using an unbiased cell-directed neuropeptide screen, we show that AVK neurons upregulate and release FMRFamide-like FLP-1 neuropeptides during infection to drive pathogen avoidance. Manipulations that increase or decrease AVK signaling accelerate or delay pathogen avoidance, respectively, implicating AVK in the dynamics of sickness behavior. FLP-1 neuropeptides act via the G-protein-coupled receptor DMSR-7 in RIM/RIC neurons to reduce tyraminergic/octopaminergic signaling that opposes pathogen avoidance. RIM/RIC neurons relay parallel signals from neuropeptides and the cytokine TGF-β that represent internal and external regulators of pathogen avoidance. Our results demonstrate that antagonism between neuromodulatory systems results in slow, graded transitions between alternative behavioral states.
“…The interneurons SMBD and SMDD were inconsistently labeled by flp-1 p(1.5 kb)::Cre and flp-1 p(513 bp)::Cre. GFP reporters made with flp - 1 p(1.5 kb) or flp-1 p(513 bp) were only expressed in AVK in larval and adult stages as shown in Figures 3C and S3C , and also shown by others (Jia and Sieburth, 2021; Li et al, 1999; Oranth et al, 2018).…”
Pathogenic infection elicits sickness behaviors that promote recovery and survival of the host. For example, following infection with the pathogenic bacterium Pseudomonas aeruginosa PA14, the nematode Caenorhabditis elegans modifies its sensory preferences to avoid the pathogen. Here we identify antagonistic neuromodulatory circuits that shape this sickness behavior. Using an unbiased cell-directed neuropeptide screen, we show that AVK neurons upregulate and release FMRFamide-like FLP-1 neuropeptides during infection to drive pathogen avoidance. Manipulations that increase or decrease AVK signaling accelerate or delay pathogen avoidance, respectively, implicating AVK in the dynamics of sickness behavior. FLP-1 neuropeptides act via the G-protein-coupled receptor DMSR-7 in RIM/RIC neurons to reduce tyraminergic/octopaminergic signaling that opposes pathogen avoidance. RIM/RIC neurons relay parallel signals from neuropeptides and the cytokine TGF-β that represent internal and external regulators of pathogen avoidance. Our results demonstrate that antagonism between neuromodulatory systems results in slow, graded transitions between alternative behavioral states.
“…It suggests that neuromodulators are likely released through non-synaptic paths ( Van Bockstaele, Colago and Valentino 1996 ; Torrealba and Carrasco 2004 ). 27.3% DCVs that near to mitochondria may result from that some mitochondria-produced hydrogen peroxide functions as signaling cue to neuropeptide releasing ( Jia and Sieburth 2021 ), or both mitochondria and DCVs are transported through microtubules to axonal terminals ( Gondre-Lewis et al., 2012 ; Mandal et al., 2021 ). Figure 3 Subcellular distributions of PAZs and DCVs in PN boutons (A–C) Subcellular distributions of PAZs (blue arrows) and DCVs (green arrows) in PN boutons.…”
“…However, low levels of ROS can serve homeostatic signaling functions, for example, increased ROS production is observed through in vitro neuronal maturation, which is correlated with enhanced OxPhos activity [ 81 , 113 , 114 ]. Additionally, mitochondrial ROS is involved in the regulation of the postsynaptic GABA receptors, strength [ 115 ], in the regulation of neuropeptide FLP-1 secretion, in C. elegans [ 116 ], in the modulation of dopamine release, in striatum of guinea pigs [ 117 ] and in the selection of inactive synapses for pruning during development in Xenopus laevis [ 118 ].…”
Section: Other Mitochondrial Functions At Synapsesmentioning
The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
