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线粒体过氧化氢在饮食诱导的氧化应激反应激活期间正向调节神经肽分泌。

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

机构信息

PIBBS program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

出版信息

Nat Commun. 2021 Apr 16;12(1):2304. doi: 10.1038/s41467-021-22561-x.

DOI:10.1038/s41467-021-22561-x
PMID:33863916
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8052458/
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 (mtHO) 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 mtHO 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. mtHO-induced FLP-1 secretion activates the oxidative stress response transcription factor SKN-1/Nrf2 in distal tissues and protects animals from ROS-mediated toxicity. mtHO 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 mtHO in linking diet-induced changes in mitochondrial homeostasis with neuropeptide secretion.

摘要

线粒体在代谢与神经递质释放的信号偶联生成中起着关键作用，但线粒体产生的 ROS 在调节神经分泌中的作用尚未被描述。在这里，我们表明源自轴突线粒体 (mtHO) 的内源性过氧化氢作为一种信号提示，选择性地调节线虫中一对中间神经元 (AIY) 的一种 FMRFamide 相关神经肽 (FLP-1) 的分泌。我们表明，增加 mtHO 水平的药理学或遗传操作会导致 FLP-1 分泌增加，这依赖于 ROS 歧化、线粒体钙内流和钙不依赖 PKC 家族成员 PKC-1 的半胱氨酸亚磺酰化。mtHO 诱导的 FLP-1 分泌激活了远端组织中的氧化应激反应转录因子 SKN-1/Nrf2，并保护动物免受 ROS 介导的毒性。AIY 神经元中的 mtHO 水平、FLP-1 分泌和 SKN-1 活性可通过使动物暴露于不同的细菌食物源而快速且可逆地调节。这些结果揭示了 mtHO 在将饮食诱导的线粒体动态平衡变化与神经肽分泌联系起来方面的一个以前未被报道的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/7d171f9faf4e/41467_2021_22561_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/4eafb71e80e7/41467_2021_22561_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/b6cc4100cb96/41467_2021_22561_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/c1edc4e22dd5/41467_2021_22561_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/a3b71f2d97e3/41467_2021_22561_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/253fdb1b6985/41467_2021_22561_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/089e0d81a8b6/41467_2021_22561_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/c7e96afc33e4/41467_2021_22561_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/7d171f9faf4e/41467_2021_22561_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/4eafb71e80e7/41467_2021_22561_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/b6cc4100cb96/41467_2021_22561_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/c1edc4e22dd5/41467_2021_22561_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/a3b71f2d97e3/41467_2021_22561_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/253fdb1b6985/41467_2021_22561_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/089e0d81a8b6/41467_2021_22561_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/c7e96afc33e4/41467_2021_22561_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39db/8052458/7d171f9faf4e/41467_2021_22561_Fig8_HTML.jpg

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