Regulation of RNA processing on the mitochondrial surface by lipid signaling

描述（由申请人提供）：线粒体，曾经被视为细胞的“简单”动力室，越来越多地被认为参与许多不同的细胞生物学过程，这些过程涉及与非线粒体细胞器如内质网和质膜的相互作用。这些相互作用部分地通过线粒体表面上产生和感测蛋白质和脂质信号的机制发生，这一直是我们在线粒体动力学（融合）和响应细胞外信号事件的能量变化的背景下关注的领域。我们最近的工作揭示了线粒体在一种特殊形式的RNA加工中的新作用，这种RNA加工似乎发生在线粒体表面和并列的RNA颗粒之间的界面上。更具体地说，我们已经将线粒体表面上的信号传导酶与第三种类型的RNAi piRNA的产生联系起来，piRNA是一种电子致密结构，称为nuage，类似于P体。使用细胞生物学，在文化和动物模型的方法，我们建议研究如何在线粒体表面的脂质信号促进线粒体和RNA加工复合物之间的这种新发现的物理和功能的相互作用，通过潜在的机制，可能包括驱动蛋白调节的运输RNA，加工颗粒和微管上的线粒体。相关性：这个最初的故事适用于精子发生的关键途径，与男性不育有关，并提供了一种新型男性避孕药的机会。然而，其他类型的RNA募集和线粒体表面的加工是已知的，并代表了一个更广泛的背景下，这种新发现的途径可能是重要的，包括与间充质干细胞，脑和心脏功能，和癌症。 公共卫生相关性：转座子的动员可导致遗传疾病，包括癌症。piRNA是发现的第三种类型的RNAi，其功能是通过抑制转座子移动和执行生殖系印记来维持基因组完整性。我们已经发现，线粒体通过锚定在线粒体表面上的信号传导酶的作用在piRNA的产生中起作用。我们建议增加我们对线粒体表面产生的信号如何调节这一过程的理解，这可能涉及控制线粒体和RNA结构如何通过微管上的细胞进行交通。如果成功，拟议的研究可以促进工具的开发，以广泛操纵基因的表观遗传结构，从而控制其表达，可能会确定男性不育的一些原因，并将为男性避孕药提供潜在的治疗机会。它也可能更广泛地重要，因为piRNA现在在许多组织中被报道。

DESCRIPTION (provided by applicant): Mitochondria, once viewed as the "simple" powerhouse of the cell, are increasingly recognized to be involved in many different cell biological processes that involve interaction with non-mitochondrial organelles such as the endoplasmic reticulum and plasma membrane. These interactions take place in part via machinery on the mitochondrial surface that generates and senses protein and lipid signals, which has been an area of focus for us in the context of mitochondrial dynamics (fusion) and changes in energetic in response to extracellular signaling events. Our recent work has uncovered a new role for mitochondria in a specialized form of RNA processing that appears to take place at the interface between the mitochondrial surface and juxtaposed RNA granules. More specifically, we have linked a signaling enzyme on the mitochondrial surface to the production of piRNAs, a third type of RNAi, in an electron-dense structure known as nuage that is similar to P-bodies. Using cell biological, in culture, and animal model approaches, we propose to study how lipid signaling at the mitochondrial surface promotes this newly identified physical and functional interaction between mitochondria and RNA-processing complexes via underlying mechanisms that potentially include kinesin-regulated trafficking of RNAs, processing granules and mitochondria on microtubules. Relevance: This initial story applies to a pathway that is critical for spermatogenesis, has relevance to male infertility, and offers opportunities fr a novel type of male contraceptive. However, other types of RNA recruitment to and processing at the mitochondrial surface are known and represent a broader context in which this newly identified pathway will likely be important, including in connection to mesenchymal stem cells, brain and cardiac function, and cancer. PUBLIC HEALTH RELEVANCE: Mobilization of transposons can cause genetic diseases including cancer. piRNAs, the third type of RNAi discovered, function to maintaining genome integrity by suppressing transposon mobilization and performing germ-line imprinting. We have found that mitochondria play a role in generation of piRNAs via the action of a signaling enzyme anchored on the mitochondrial surface. We propose to increase our understanding of how a signal generated on the mitochondrial surface regulates this process, which may involve controlling how mitochondria and the RNA structures traffic through the cell on microtubules. If successful, the proposed research could facilitate the development of tools to broadly manipulate the epigenetic structure of genes and thus control their expression, might identify some causes of male infertility, and will present a potential therapeutic opportunity for a male contraceptive. It may also be important more broadly, as piRNAs are now being reported in many tissues.