Metabolic regulation by p66Shc determines stem cell fate and neuronal survival

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Mammalian cells used specialized organelles called mitochondria to break down nutrients and generate high levels of ATP, a chemical form of energy, in a process dependent on the presence of oxygen. However, oxygen radicals are potentially harmful by-products that arise during mitochondrial metabolism. During the aging process, mammals frequently exhibit increased production of oxygen radicals, or the decreased ability to detoxify them, particularly in specialized brain cells called neurons. Due to their high metabolic state, neurons are particularly vulnerable to mitochondrial generated oxygen radicals. Thus, neurons in the brain must be able to mount a sufficient antioxidant defense to maintain survival throughout one's lifespan. Alternatively, to replenish neuron cell death, adult stem cells can give rise to functional neurons, in a process called differentiation. The precise regulation of stem cell differentiation, and antioxidant defense in neurons, is critical to maintain brain function throughout life. Recent studies have shown that a unique signaling protein called p66Shc can move from the cytosol, the main fluid containing portion of a cell, into mitochondria following exposure to certain forms of stress. Once in the mitochondria, p66Shc triggers increased oxygen radical formation that can then promote a variety of outcomes, including neuronal differentiation or cell death. However, the precise mechanism by which p66Shc controls these cellular processes is poorly understood. Recent studies in my lab have revealed that p66Shc can act as a "switch" which turns off glycolysis, a form of metabolism that does not generate oxygen radicals, while turning on mitochondrial metabolism. In addition, p66Shc also suppresses the activation of a key protein called Nrf2 that is required for expression of antioxidant genes. Using both cultured mouse embryonic stem cells and neuron-like cells, we will explore the hypothesis that p66Shc induced mitochondrial metabolism and oxygen radical production affects the ability of stem cells to differentiate, and form neurons to mount an appropriate antioxidant response. In addition, we will identify the types of specific proteins that become oxidatively modified in response to p66Shc induced oxygen radical production. As a long-term goal, we will also generate mice in which the p66Shc gene is deleted in either adult brain stem cells or neurons. The results of the proposed study will provide novel insight into the molecular mechanisms controlling stem cell differentiation and how neurons respond to stress; events critical for optimal brain function throughout life.