Axonal Mitochondria Modulate Neuropeptide Secretion Through the Hypoxic Stress Response in Caenorhabditis elegans

Neurons are highly dependent on mitochondrial function, and mitochondrial damage has been implicated in many neurological and neurodegenerative diseases. Here we show that axonal mitochondria are necessary for neuropeptide secretion in Caenorhabditis elegans and that oxidative phosphorylation, but not mitochondrial calcium uptake, is required for secretion. Oxidative phosphorylation produces cellular ATP, reactive oxygen species, and consumes oxygen. Disrupting any of these functions could inhibit neuropeptide secretion. We show that blocking mitochondria transport into axons or decreasing mitochondrial function inhibits neuropeptide secretion through activation of the hypoxia inducible factor HIF-1. Our results suggest that axonal mitochondria modulate neuropeptide secretion by regulating transcriptional responses induced by metabolic stress.