Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response inC. elegans

Abstract

AbstractThe gut-brain axis mediates bidirectional signaling between the intestine and the nervous system and is critical for organism-wide homeostasis. Here we report the identification of a peptidergic endocrine circuit in which bidirectional signaling between neurons and the intestine potentiates the activation of the antioxidant response inC. elegans.We identify a FMRF-amide-like peptide, FLP-2, whose release from the intestine is necessary and sufficient to activate the intestinal oxidative stress response by promoting the release of the antioxidant FLP-1 neuropeptide from neurons. FLP-2 secretion from the intestine is positively regulated by endogenous hydrogen peroxide (H2O2) produced in the mitochondrial matrix bysod-3/superoxide dismutase, and is negatively regulated byprdx-2/peroxiredoxin, which depletes H2O2in both the mitochondria and cytosol. H2O2promotes FLP-2 secretion through the DAG and calcium-dependent protein kinase C family memberpkc-2and by the SNAP25 family memberaex-4in the intestine. Together, our data demonstrate a role for intestinal H2O2in promoting inter-tissue antioxidant signaling through regulated neuropeptide-like protein exocytosis in a gut-brain axis to activate the oxidative stress response.