The mitochondrial unfolded protein response (UPR^mt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In Caenorhabditis elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPR^mt The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues are not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein-coupled receptor, FSHR-1, in promoting UPR^mt activation. Genetic deficiency of fshr-1 severely attenuates UPR^mt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPR^mt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPR^mt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell nonautonomously in neurons to activate UPR^mt upstream of SPHK-1 signaling in the intestine.

中文翻译：

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FSHR-1/GPCR 调节秀丽隐杆线虫线粒体未折叠蛋白反应。

线粒体未折叠蛋白反应（UPR ^mt）是一种进化上保守的适应性反应，其功能是在线粒体损伤后维持线粒体稳态。在秀丽隐杆线虫中，神经系统通过释放内分泌信号作用于远端组织以激活 UPR ^mt，在应对线粒体应激方面发挥着核心作用。神经元感知线粒体应激并将其传递到远端组织的机制尚不完全清楚。^{在这里，我们确定了保守的促卵泡激素 G 蛋白偶联受体 FSHR-1 在促进 UPR mt}激活中的作用。fshr-1的遗传缺陷严重削弱了 UPR ^{mt 的}激活和整个生物体对线粒体应激的反应。FSHR-1 与 SPHK-1/鞘氨醇激酶在共同的遗传途径中发挥作用，促进 UPR ^mt激活，并且 FSHR-1 调节肠道中 SPHK-1 的线粒体关联。通过组织特异性救援测定，我们表明 FSHR-1 在神经元中发挥作用，激活 UPR ^mt，促进肠道中 SPHK-1 的线粒体结合，并促进整个生物体响应线粒体应激而生存。我们认为 FSHR-1 在神经元中非自主地发挥细胞功能，激活肠道中 SPHK-1 信号传导上游的UPR ^{mt 。}