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

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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.