p66Shc mediated effects on ROS signaling and cytoskeletal remodeling

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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 order to generate ATP, mitochondria consume oxygen while at the same time producing carbon dioxide and water. 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. The mechanism responsible for increased mitochondrial radical production that occurs with age is poorly understood. Interestingly, loss of the p66Shc gene in mice results in increased tolerance to oxidant exposure and extended lifespan. Recent studies have shown that the p66Shc protein 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 thereby promoting a series of changes including alterations in cell shape, movement and, in certain circumstances, cell death. These observations indicate that p66Shc is a major regulator of oxygen radical production, oxidant sensitivity, cell morphology and organismal aging. However the precise mechanism by which p66Shc controls these processes is poorly understood. Using a variety of novel techniques developed in my lab we will explore the hypothesis that p66Shc induced oxygen radical production in cultured neuronal cell lines leads to oxidation of specific proteins which control cell morphology, movement and signaling processes. We believe that oxidation of these proteins lead to altered protein activity and compromised neuronal function with age. The results of the proposed study will provide novel insight into the molecular mechanisms controlling the aging process in neurons.