神經胜肽訊號調控線蟲粒線體壓力反應與形態

Abstract

不同的胞器有獨特的壓力反應能夠啟動一連串的保護機制，使生物體適應外界或內在的變動。近期許多研究顯示，神經系統可以透過傳遞神經訊號調控全身性的壓力反應。在秀麗桿狀線蟲Caenorhabditis elegans中，當神經細胞內粒線體功能被破壞時，會藉由血清素與神經胜肽調控全身性的粒線體壓力反應。研究發現，線蟲的神經細胞能夠透過改變粒線體的動態平衡，來影響線蟲全身所有細胞的粒線體壓力反應。在神經系統中，抑制粒線體融合蛋白FZO-1/Mitofusin時，有兩個類胰島素胜肽INS-27和INS-35參與在協調粒線體壓力反應以及粒線體的動態平衡之中。當神經細胞的粒線體動態平衡被破壞時，除了引發粒線體的壓力反應，更會造成腸道的粒線體形態破碎。我們更進一步發現，類胰島素生長因子的受體DAF-2作用在神經細胞完成這個調控。此外，神經系統動態平衡改變引起的粒線體壓力反應，會增加線蟲對抗綠膿桿菌的能力，證明神經細胞在協調系統性粒線體壓力反應的重要性。本篇研究顯示，神經細胞中粒線體的動態平衡與粒線體的壓力反應之間的協調，能夠給予線蟲在面對致病菌感染時有生存上的益處。

Cells mount organelle-specific stress responses to restore proteomic homeostasis and adapt to various stressors. Cellular stress responses can be regulated in a non-autonomous fashion via neuronal signaling. In C. elegans, mitochondrial perturbation in the nervous system induces systemic mitochondrial unfolded protein response (UPRmt) through serotonin and the FLP-2 neuropeptide. In addition to UPRmt, we find that mitochondrial dynamics are coordinated among C. elegans somatic tissues through neuronal signaling. Here we characterize two insulin-like peptides in inter-tissue coordination of UPRmt and mitochondrial dynamics upon depletion of the mitochondrial fusion gene fzo-1 in neurons. Neuronal fzo-1 RNAi elicits non-autonomous UPRmt and also induces mitochondrial fragmentation in non-neural tissues. We find that the insulin-like peptides INS-27 and INS-35 act to coordinate UPRmt and mitochondrial dynamics between neurons and other somatic tissues, and they likely signal through DAF-2, the insulin-like growth factor 1 receptor. Our data show that DAF-2 acts in neurons to regulate UPRmt induction. Non-autonomous UPRmt induced by neuronal mitochondrial perturbation improves resistance to pathogenic bacteria, confirming the importance of neural coordination of systemic UPRmt. Our study indicates that coordination of neuronal mitochondrial dynamics and systemic mitochondrial states confers survival benefit under pathogenic bacterial infection.