Sphingolipid signaling in mitochondrial surveillance

项目摘要 鞘脂调节多种细胞和生理过程以及鞘脂的失调 信号与心血管和神经退行性疾病以及中风有关。长期的 这项拟议的研究的目标是确定鞘氨醇-Sphingosine- 1-磷酸(S1P)由鞘氨醇激酶产生，调节未折叠的线粒体的激活 蛋白质反应(UPRmt)。UPRmt是维持线粒体蛋白质稳态的关键。 对线粒体应激的反应，但其激活的分子机制尚不完全 明白了。我的实验室使用线虫模型来研究鞘脂信号在 调节神经功能和神经递质释放。我们最近发现了一种新的函数 唯一的鞘氨醇激酶同源蛋白SPHK-1在激活UPRmt和促进整个生物体中的作用 对一系列线粒体应激源的保护作用。我们发现SPHK-1与 这种联系是由线粒体应激产生的 自主地(在肠道中)或非自主地(通过神经系统)细胞。在这里，我们试图 揭示神经鞘脂信号调节的细胞和分子机制 UPRmt，它是如何激活UPRmt的，以及它是如何影响线粒体动态平衡和存活的 多细胞生物。在目标1中，我们确定了线粒体应激的分子机制 调节SPHK-1的靶向和功能。在目标2中，我们确定了神经内分泌信号如何调节 UPRmt期间的鞘脂信号。在目标3中，我们确定了UPRmT期间S1P的细胞靶点 它们如何调节转录反应以确保适当的细胞稳态和面部存活 压力的影响。这一提议将促进对线粒体鞘氨醇激酶如何 在体内被调控和发出信号，并将进一步了解激活的机制 UPRmt。

Project Summary Sphingolipids regulate a multitude of cellular and physiological processes and dysregulation of sphingolipid signaling is associated with cardiovascular and neurodegenerative disorders, and stroke. The long-term goal of the proposed research is to identify the cellular and molecular mechanisms by which sphingosine- 1-phospate (S1P), generated by sphingosine kinase, regulates the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt is critical for maintaining mitochondrial protein homeostasis in response to mitochondrial stress, but molecular mechanisms underlying its activation are not fully understood. My laboratory uses the model C. elegans to study the role of sphingolipid signaling in regulating neuronal function and neurotransmitter release. We recently uncovered a novel function for the sole sphingosine kinase ortholog, SPHK-1, in activating the UPRmt and in promoting organism-wide protection in response to a broad array of mitochondrial stressors. We found that SPHK-1 associates with mitochondria and that this association is regulated by mitochondrial stress generated either cell autonomously (in the intestine) or cell non-autonomously (by the nervous system). Here we seek to uncover the cellular and molecular mechanisms by which sphingolipid signaling is regulated during the UPRmt, how it activates the UPRmt and how it impacts mitochondrial homeostasis and survival in multicellular organisms. In Aim 1, we determine the molecular mechanism by which mitochondrial stress regulates SPHK-1 targeting and function. In Aim 2, we determine how neuroendocrine signaling regulates sphingolipid signaling during the UPRmt. In Aim 3, we identify cellular targets of S1P during the UPRmt and how they regulate transcriptional responses to ensure proper cellular homeostasis and survival in the face of stress. This proposal will advance mechanistic understanding of how mitochondrial sphingosine kinase is regulated and signals in vivo, and will further understanding of the mechanism underlying activation of the UPRmt.