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Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response

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  • Qi Jia

    (PIBBS program, Keck School of Medicine, University of Southern California)

  • Derek Sieburth

    (Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California)

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 manipulations that increase mtH2O2 levels lead to increased FLP-1 secretion that is dependent upon ROS dismutation, mitochondrial calcium influx, and cysteine sulfenylation of the calcium-independent PKC family member PKC-1. mtH2O2-induced FLP-1 secretion activates the oxidative stress response transcription factor SKN-1/Nrf2 in distal tissues and protects animals from ROS-mediated toxicity. mtH2O2 levels in AIY neurons, FLP-1 secretion and SKN-1 activity are rapidly and reversibly regulated by exposing animals to different bacterial food sources. These results reveal a previously unreported role for mtH2O2 in linking diet-induced changes in mitochondrial homeostasis with neuropeptide secretion.

Suggested Citation

  • Qi Jia & Derek Sieburth, 2021. "Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22561-x
    DOI: 10.1038/s41467-021-22561-x
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    Cited by:

    1. Ichiro Aoki & Luca Golinelli & Eva Dunkel & Shripriya Bhat & Erschad Bassam & Isabel Beets & Alexander Gottschalk, 2024. "Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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