線蟲神經系統調控粒線體壓力反應的分子機制

Abstract

逆境或外在壓力導致生物體內蛋白構型異常時，細胞會透過專一性的訊號傳遞機制，進行各不同胞器獨特的生理反應，藉以去除構型異常的失能蛋白或將蛋白的構型恢復正常，這些統稱為胞器內未摺疊蛋白反應 (UPR)，其中包含了細胞質的熱休克反應(HSR)和內質網(UPRER)和粒線體的未摺疊蛋白反應(UPRmt)。生物體的老化會造成蛋白恆定態的失衡或粒線體功能異常，除伴隨著細胞生理功能的下降，也可能引起異常的未摺疊蛋白反應。前人在秀麗桿狀線蟲Caenorhabditis elegans當中發現，神經細胞內粒線體的呼吸狀態會影響線蟲全身性的粒線體蛋白平衡，但是神經細胞內與不同細胞間訊息傳遞的分子機制尚不清楚。本篇研究發現線蟲中調控粒線體融合的蛋白FZO-1/Mitofusin可以影響粒線體未折疊蛋白反應。fzo-1基因的突變引發多形性的性狀，包含生長遲緩、生殖能力下降、神經老化加速和粒線體未摺疊蛋白反應的異常上升。我們發現在神經細胞內專一表現FZO-1，除可以改善神經內粒線體型態的缺失和神經元細胞的過度老化外，亦可以有效改善fzo-1突變所引發的全身性粒線體未摺疊蛋白反應的異常上升，及減緩fzo-1突變所引發的生長遲緩。在腸道內專一表現FZO-1則可改善粒線體未摺疊蛋白反應在腸細胞內的異常上升。本篇研究發現神經細胞內粒線體型態的調控可以影響全身粒線體蛋白的平衡，有助於了解神經細胞內粒線體如何透過訊號傳遞來調控全身粒線體蛋白的平衡和生物體老化過程中蛋白質的恆定性。

Compartment-specific stress responses, including cytosolic heat shock response (HSR), the endoplasmic reticulum unfolded protein response (UPRER), and the mitochondrial unfolded protein response (UPRmt), protect animals against proteotoxic stress. Age-dependent decline in cellular functions and organismal physiology is associated with dysregulated protein homeostasis and mitochondrial function. Systemic proteostasis in the nematode Caenorhabditis elegans could be regulated by mitochondrial respiration in the neurons, but the molecular mechanisms of such intercellular control of protein homeostasis remains unclear. Here we report that the C. elegans mitochondrial fusion protein FZO-1/Mitofusin controlled UPRmt in a cell non-autonomous manner. Mutations of fzo-1 caused pleiotropic phenotypes, including slow development, reduced fecundity, accelerated neuronal aging, and maladapted UPRmt. Neuronal mitochondrial defects and aging signs of the neurites were rescued by neuron-autonomous FZO-1 functions. The maladapted UPRmt in the intestine was moderately rescued by intestinal FZO-1 expression. Unexpectedly, aberrant intestinal UPRmt of the fzo-1 mutants was significantly ameliorated by neuronal FZO-1. Neuronal FZO-1 also partially rescued the slow development of the fzo-1 mutant. We are now exploring neuron-derived signals that potentially mediate such non-autonomous effects on systemic mitochondrial proteostasis. Progress in this proposal could further our understanding of how mitochondria-mediated, neuron-derived signals control systemic protein homeostasis and cellular aging at the organismal level.