Characterization of a mitochondrial redox switch regulating cell growth, stress resistance, and metabolism

线粒体是“细胞的发电站”，负责将能量转化为细胞可以使用的形式。线粒体为体内的所有细胞提供这种可用的能量;肌肉细胞用它来收缩，神经元用它来产生电脉冲，皮肤细胞需要它来分裂。 线粒体通过一个受控的多步骤过程来氧化我们食物中的分子来完成这一任务。在这种“氧化磷酸化”过程中，线粒体产生大量的氧自由基，这些氧自由基可以与线粒体内部以及细胞其他部分的许多物质相互作用。我们现在知道这些氧自由基在细胞生理学中有特定的作用。最近，我们已经开始了解它们如何影响细胞的分裂能力，甚至细胞的存活能力。细胞分裂和生存能力对多细胞生物的生命至关重要。细胞分裂异常是癌症的标志，神经元等细胞的死亡会导致神经退行性变。 因此，线粒体氧自由基的这些作用也很重要。 我们已经发现，雌激素和植物雌激素引起线粒体产生氧自由基的重大修改，这对细胞功能有重大影响。 在这份拨款申请中，我描述了我打算如何进一步理解这一过程。我将研究两种特定的植物雌激素，白藜芦醇和紫檀芪，我们以前已经证明，通过雌激素受体的工作。我将确切地确定它们如何改变线粒体氧自由基的产生，以及细胞内发生了什么变化。这项工作的大部分是使用在培养中生长的哺乳动物细胞完成的，在那里它们的行为和功能可以使用非常高分辨率的显微镜进行可视化。 然后将使用实验室小鼠收集少量数据，以确认我们在培养皿中生长的细胞中看到的情况也发生在活动物中。 我们收集的信息最终将提供科学知识的基础，其他人将使用这些知识来开发治疗癌症和某些代谢疾病的新策略。我们的数据和出版物/演示文稿将从这项工作中产生，也将有助于白藜芦醇和紫檀芪作为营养保健品的发展，为所有加拿大人带来新产品，新工作和新应用。

Mitochondria are the `powerhouse of the cell', responsible for converting energy into a form that our cells can use. Mitochondria provide this usable energy to all cells in the body; muscle cells use it to contract, neurons use it to produce electrical impulses, and skin cells need it to divide.  Mitochondria accomplish this task using a controlled multistep process for oxidizing molecules that originate in our food. During this `oxidative phosphorylation' mitochondria produce significant amounts of oxygen free radicals that can interact with many things inside of mitochondria and also within the rest of the cell. We now understand that these oxygen radicals have specific roles in cell physiology. Recently, we have begun to understand how they affect a cell's ability to divide and even a cell's ability to remain alive. Cell division and viability are critical to the life of multicellular organisms. Aberrant cell division is the hallmark of cancer and the death of cells like neurons leads to neurodegeneration. Thus, these roles of mitochondrial oxygen radicals are also important. We have discovered that estrogens and phytoestrogens cause a major modification in mitochondrial production of oxygen radicals and that this has major effects on cell functions. In this grant proposal I describe how I intend to further our understanding of this process. I will investigate two specific phytoestrogens, resveratrol and pterostilbene, that we have previously shown to work via estrogen receptors. I will determine exactly how they alter mitochondrial oxygen radical production and what changes occur within cells as a result. Most of this work is done using mammalian cells grown in culture, where their behaviours and functions can be visualized using a very high resolution microscope. A small amount of data will then be collected using laboratory mice, to confirm that what we see in cells growing in dishes also occurs in live animals. The information we gather will ultimately provide the basic foundation of scientific knowledge that others will use to develop new strategies to treat cancer and certain metabolic diseases in people. Our data and the publications/presentations that will arise from this work will also aid in the development of resveratrol and pterostilbene as nutraceuticals, leading to new products, new jobs and new applications for the benefit of all Canadians.**