Regulation of In Vivo Mitochondrial Energetics by Oxidative Stress throughout Life: A Multi-Modal Spectroscopy Approach

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Regulation of In Vivo Mitochondrial Energetics by Oxidative Stress throughout Life: A Multi-Modal Spectroscopy Approach

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Title: Regulation of In Vivo Mitochondrial Energetics by Oxidative Stress throughout Life: A Multi-Modal Spectroscopy Approach
Author: Siegel, Michael
Abstract: Age-related skeletal muscle degeneration contributes to lost quality of life and an increased health care burden for the aging population. At the crossroads of energy production, cell signaling, and free-radical production, mitochondria are implicated in this loss of skeletal muscle function with age. Here we test the hypothesis that in vivo mitochondrial function is depressed in old organisms as a result of reversible modulation by oxidative stress rather than irreversible accumulation of oxidative damage to proteins, lipids, and DNA. Oxidative stress-induced reduction of mitochondrial coupling efficiency has been implicated as a negative feedback mechanism responsible for mitigating mitochondrial reactive oxygen species production, and provides a possible link between age-related oxidative stress and age-related loss of function. To measure in vivo mitochondrial energetics on a timescale compatible with fluctuations in oxidative stress, we present a multi-modal system for simultaneous measurements of metabolite concentrations using 31P magnetic resonance spectroscopy and tissue oxygenation using near infrared optical spectroscopy in mouse skeletal muscle. Using this technique we demonstrate the reduction of mitochondrial coupling efficiency (P/O ratio) in a pharmacological (paraquat treatment) model of oxidative stress in the absence of intrinsic mitochondrial defects, with a similar responses in genetic (CuZn-superoxide dismutase knock-out and glutathione deficient) models. We find that this phenomenon persists throughout life, but that the energetic consequences of depressed mitochondrial efficiency become amplified by age. By treating old mice with the mitochondrial-targeted antioxidant SS31 we demonstrate that depressed mitochondrial function is a reversible phenomenon of aging, as mitochondrial energetics were rapidly restored to young levels. SS31-treatment also improved in situ muscle fatigue and live endurance capacity in old mice, indicating that the rapid recovery of mitochondrial energetics has important implications for improving physical ability of aged organisms. This work demonstrates a powerful new technology for measuring acute metabolic changes in vivo, a new way of thinking about age-related functional losses, and a promising suggestion that targeting mitochondrial oxidative stress with SS31 will have therapeutic benefits for aging humans.
Description: Thesis (Ph.D.)--University of Washington, 2012
URI: http://hdl.handle.net/1773/20899
Author requested restriction: No embargo

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