線蟲神經系統中粒線體動態平衡調控粒線體壓力反應和型態

Non-Autonomous Regulation of Mitochondrial Stress Response and Morphology by Neuronal fzo-1/Mitofusin in C.elegans

林良憶(Liang-Yi Lin)

指導教授 ： 潘俊良

國立臺灣大學/醫學院/分子醫學研究所/碩士(2017年)

https://doi.org/10.6342/NTU201703583

摘要

當遭遇到環境壓力時，生物體內有感應的分子機制在不同胞器中產生相對應的保護反應，稱之為胞器內未摺疊蛋白反應 (UPR)。研究也發現當神經系統遭遇到壓力，能藉由神經訊號產生全身性的胞器內未摺疊蛋白反應，顯示此保護機制能夠被神經訊號所調控。當粒線體的呼吸作用受到抑制或是粒線體中蛋白質穩定失衡，會引發粒線體的未摺疊蛋白反應 (UPRmt)。近來的研究顯示神經系統藉由分泌血清素和神經胜肽FLP-2來調控粒線體的未摺疊蛋白反應。在本篇研究中發現，藉由抑制神經系統中秀麗桿狀線蟲Caenorhabditis elegans調控粒線體的聚合蛋白FZO-1/Mitofusin來破壞神經細胞中的粒線體動態平衡，會引發全身性的粒線體的未摺疊蛋白反應和造成腸道的粒線體型態破碎。並發現乙醯膽鹼、麩胺酸、酪胺、神經胜肽都參與在粒線體的未摺疊蛋白反應中，其中來自RIC和RIM神經的酪胺透過受器TYRA-3完成下游的調控。腸道中粒線體型態改變則是受到神經胜肽而非神經傳導物質鎖調控，暗示這兩種生理現象可能是由不同的神經迴路調控。而我們正在研究神經系統動態平衡改變引起的粒線體未摺疊蛋白反應，參與在何種生理狀態調控和其的生理意義。

關鍵字

線蟲 ； 粒線體 ； 粒線體聚合蛋白FZO-1/Mitofusin ； 粒線體未摺疊蛋白反應 ； 粒線體型態 ； 神經內分泌訊號

並列摘要

Tissue-specific stress responses are protective mechanisms against proteotoxic stress and could be regulated in a non-autonomous fashion. Inhibition of mitochondrial respiration or proteostasis triggers systemic mitochondrial unfolded protein response (UPRmt), and recently serotonin and the FLP-2 neuropeptide had been shown to be important for this regulation. Here we report that disrupting mitochondrial dynamics in the neurons, by silencing the mitochondrial fusion gene fzo-1, induced UPRmt and mitochondrial fragmentation in the intestine. Acetylcholine, tyramine, glutamate and neuropeptides were required to mediate non-autonomous UPRmt. Our data suggest that tyramine signals derived from the RIM and RIC neurons target neurons that express the TYRA-3 tyramine receptor. Strikingly, neuropeptides, but not neurotransmitters, are important for non-autonomous regulation of mitochondrial dynamics in non-neural tissues. Consistent with previous studies linking UPRmt and bacterial defense, fzo-1 mutants showed avoidance to bacterial food. We are now exploring the neural mechanisms that link mitochondrial dynamics to non-autonomous UPRmt regulation and pathogen avoidance.

並列關鍵字

C. elegant ； Mitochondria ； FZO-1/Mitofusin ； Mitochondrial unfolded protein response ； Mitochondrial morphology ； Neuroendocrine signals

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