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

线粒体是“细胞的发动机”，负责将能量转化为我们的细胞可以使用的形式。线粒体为体内所有细胞提供这种可用能量；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。线粒体使用受控的多步骤过程来氧化起源于我们食物的分子来完成这一任务。在这种“氧化磷酸化”过程中，线粒体会产生大量的氧自由基，这些氧自由基可以与线粒体内的许多物质相互作用，也可以与细胞的其他部分相互作用。我们现在了解到，这些氧自由基在细胞生理学中具有特定的作用。最近，我们已经开始了解它们如何影响细胞的分裂能力，甚至细胞保持存活的能力。细胞分裂和活性对多细胞生物体的生命至关重要。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化。因此，线粒体氧自由基的这些作用也很重要。我们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改变，这对细胞功能有重大影响。在这份赠款提案中，我描述了我打算如何加深我们对这一进程的理解。我将研究两种特定的植物雌激素，白藜芦醇和蕨类化合物，我们之前已经证明它们是通过雌激素受体起作用的。我将确切地确定它们如何改变线粒体氧自由基的产生，以及由此在细胞内发生的变化。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用非常高分辨率的显微镜可视化。然后，将使用实验室小鼠收集少量数据，以证实我们在培养皿中生长的细胞中看到的东西也在活动物中发生。我们收集的信息最终将提供科学知识的基本基础，其他人将利用这些基础来开发治疗癌症和某些人类代谢性疾病的新策略。我们的数据和这项工作将产生的出版物/介绍也将有助于开发白藜芦醇和蕨类作为保健食品，从而为所有加拿大人带来新产品、新就业机会和新应用。

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.