The goal of this project is to define the interactions of selenium and vitamins C and E in preventing oxidant damage. Vitamin C recycles and thus preserves vitamin E or alpha-tocopherol in cell membranes. We showed that the selenoenzyme thioredoxin reductase, which is present in both cytosol and mitochondria, recycles vitamin C from both its oxidized forms. We hypothesize that thioredoxin reductase and vitamin C spare vitamin E in part through these mechanisms, and that vitamin C and other selenoenzymes also directly consume radicals that would otherwise oxidize vitamin E. This hypothesis is supported by two in vivo guinea pig models developed in the first project period. In one model, a combined deficiency of vitamins E and C produces rapidly fatal central nervous system (CNS) dysfunction. In the other model, a combined deficiency of vitamin E and selenium causes a rapidly fatal myopathy. In the latter model, mitochondrial degeneration precedes muscle necrosis. This suggests that mitochondrial integrity depends on adequacy of both vitamin E and selenium. In this project, we will test this hypothesis directly, and determine as well whether vitamin C contributes to mitochondrial function and defense against oxidant stress. Given the recent evidence that mitochondrial dysfunction leads to apoptosis, assessing the role of antioxidant vitamins and selenium in protecting mitochondria from oxidant damage will have relevance for aging and human diseases, such as atherosclerosis and neurodegenerative disorders. There are four specific aims involving guinea pigs, which, like humans, cannot synthesize vitamin C de novo. Prompted by the results of the in vivo model of combined deficiencies of vitamin E and selenium, the first three aims involve studies in mitochondria prepared from guinea pig muscle. In the first aim, uptake, recycling, function, and antioxidant role of vitamin C in mitochondria will be assessed. In the second aim, the distribution, recycling, and antioxidant function of vitamin E in mitochondria will be determined. In the third aim, the role of selenium in preventing mitochondrial oxidant damage will be assessed. In the fourth aim, the specificity of different forms of vitamin E in preventing muscle and CNS damage will be determined in vitamin E-deficient guinea pigs. Whether selenium and ascorbate spare vitamin E in vivo will also be assessed. Using this approach, it will be possible to relate the crucial, mitochondrial functions of selenium and vitamins C and E to the antioxidant defenses of the whole animal.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Nutrition Study Section (NTN)
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Finkelstein, David B
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Hill, Kristina E; Motley, Amy K; May, James M et al. (2009) Combined selenium and vitamin C deficiency causes cell death in guinea pig skeletal muscle. Nutr Res 29:213-9
May, James M; Li, Liying; Qu, Zhi-Chao et al. (2007) Mitochondrial recycling of ascorbic acid as a mechanism for regenerating cellular ascorbate. Biofactors 30:35-48
Burk, Raymond F; Christensen, Joani M; Maguire, Mark J et al. (2006) A combined deficiency of vitamins E and C causes severe central nervous system damage in guinea pigs. J Nutr 136:1576-81
Huang, Junjun; May, James M (2003) Ascorbic acid spares alpha-tocopherol and prevents lipid peroxidation in cultured H4IIE liver cells. Mol Cell Biochem 247:171-6
Hill, Kristina E; Montine, Thomas J; Motley, Amy K et al. (2003) Combined deficiency of vitamins E and C causes paralysis and death in guinea pigs. Am J Clin Nutr 77:1484-8
Jones, Wright; Li, Xia; Qu, Zhi-chao et al. (2002) Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med 33:83-93
Li, Xia; Cobb, Charles E; May, James M (2002) Mitochondrial recycling of ascorbic acid from dehydroascorbic acid: dependence on the electron transport chain. Arch Biochem Biophys 403:103-10
May, James M; Morrow, Jason D; Burk, Raymond F (2002) Thioredoxin reductase reduces lipid hydroperoxides and spares alpha-tocopherol. Biochem Biophys Res Commun 292:45-9
Li, X; Hill, K E; Burk, R F et al. (2001) Selenium spares ascorbate and alpha-tocopherol in cultured liver cell lines under oxidant stress. FEBS Lett 508:489-92
Li, X; Cobb, C E; Hill, K E et al. (2001) Mitochondrial uptake and recycling of ascorbic acid. Arch Biochem Biophys 387:143-53

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