Mitochondria cell-autonomously regulate the secretion of neuropeptides in C. elegans.
Neurons are hard-working cells that need a lot of energy to do their jobs, so it’s no surprise that they are highly dependent on their mitochondria to function properly. Yet these organelles do much more for cells than simply produce energy. In GENETICS, Zhao et al. report on how mitochondria are directly involved in regulating the secretion of neuropeptides.
In a previous paper, the authors found that disruption of the gene ric-7 caused decreased neuropeptide secretion and locomotion defects in C. elegans—but the mechanism underlying these phenotypes was unclear because little was known about the function of ric-7. After another group demonstrated that ric-7 is required for the long-distance transportation of mitochondria from the neuron’s cell body into its axons, Zhao and colleagues hypothesized that disrupting mitochondrial transport might be the mechanism by which ric-7 defects cause neuronal phenotypes.
To test this, the authors expressed a chimeric kinesin construct, kin-Tom7, in ric-7 mutant axons. This chimera is a kinesin protein fused to a mitochondrial membrane protein. A prior study showed that kin-Tom7 restored transport of mitochondria to the axons of ric-7 mutants but did not affect other cellular functions. The authors showed that kin-Tom7 also rescues the ric-7 mutation-impaired neuropeptide secretion and locomotion defects, suggesting that improper mitochondrial transport was indeed the cause of neuronal defects in ric-7 mutants.
Because mitochondria are involved in so many cellular processes, the authors wondered which function(s) of axonal mitochondria might be necessary for neuropeptide secretion. Using selected mutant worms, they found that disrupting oxidative phosphorylation decreased neuropeptide secretion—but impairing mitochondrial calcium uptake didn’t.
Impaired oxidative phosphorylation can cause increased levels of reactive oxygen species (ROS) and hypoxia, so the authors suspected that these stress states might be involved in neuropeptide secretion. Indeed, they found that impairing the function of ROS detoxification enzymes—an alternative way to increase ROS—and growth in hypoxic conditions both led to decreased neuropeptide secretion.
Further investigation showed that the effects of axonal mitochondria on neuropeptide secretion were mediated by the hypoxia-inducible factor HIF-1, which is central to the response to hypoxia in C. elegans. Worms with constitutively active HIF-1 had lower secretion of neuropeptides, but this could be reversed by turning HIF-1 “off” again through other transgenic manipulations. Crucially, combining the constitutively active HIF-1 with the ric-7 defect in a double mutant had no additional phenotypic effects, suggesting the two proteins act in the same pathway. Consistent with this, hif-1 null mutations restored neuropeptide secretion in ric-7 mutants.
Together, these results support the idea that mitochondria regulate neuropeptide secretion in part by modulating ROS production and the hypoxic stress response. These findings could provide a mechanism by which the biochemical conditions within a neuron alter communication between neurons to trigger more widespread changes in the nervous system.
CITATION:
Tongtong Zhao, Yingsong Hao, Joshua M. Kaplan
Genetics September 2018 210: 275-285; https://doi.org/10.1534/genetics.118.301014
Science Writing and Communications Intern, Genetics Society of America.
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