Abstract
Vitamin E is the major lipid-soluble chain-breaking antioxidant in mammals and plays an important role in normal development and physiology. Deficiency (whether dietary or genetic) results in primarily nervous system pathology, including cerebellar neurodegeneration and progressive ataxia (abnormal gait). However, despite the widely acknowledged antioxidant properties of vitamin E, only a few studies have directly correlated levels of reactive oxygen species with vitamin E availability in animal models. We explored the relationship between vitamin E and reactive oxygen species in two mouse models of vitamin E deficiency: dietary deficiency and a genetic model (tocopherol transfer protein, Ttp-/- mice). Both groups of mice developed nearly complete depletion of alpha-tocopherol (the major tocopherol in vitamin E) in most organs, but not in the brain, which was relatively resistant to loss of alpha-tocopherol. F4-neuroprostanes, an index of lipid peroxidation, were unexpectedly lower in brains of deficient mice compared with controls. In vivo oxidation of dihydroethidium by superoxide radical was also significantly lower in brains of deficient animals. Superoxide production by brain mitochondria isolated from vitamin E-deficient and Ttp-/- mice, measured by electron paramagnetic resonance spectroscopy, demonstrated a biphasic dependence on exogenously added alpha-tocopherol. At low concentrations, alpha-tocopherol enhanced superoxide flux from mitochondria, a response that was reversed at higher concentrations. Here we propose a mechanism, supported by molecular modeling, to explain decreased superoxide production during alpha-tocopherol deficiency and speculate that this could be a beneficial response under conditions of alpha-tocopherol deficiency.
Highlights
␣-Tocopherol was first discovered as a micronutrient indispensable for reproduction in female rats [1]
The two human congenital syndromes that result in severe vitamin E deficiency, abetalipoproteinemia, caused by deletion mutations in the apolipoprotein B gene, and AVED, resulting from deletion mutations in the ␣-tocopherol transfer protein (TTP) gene, result in severe progressive cerebellar degeneration, ataxia, loss of deep tendon reflexes, and a number
Of other neurological manifestations, with minimal pathology outside the nervous system [19]. This indicates that the brain may be uniquely sensitive to ␣-tocopherol deficiency. Both of these deficiency syndromes can be improved by high dose vitamin E therapy, confirming that ␣-tocopherol deficiency is key to the nervous system pathology
Summary
␣-Tocopherol was first discovered as a micronutrient indispensable for reproduction in female rats [1]. Effects of ␣-Tocopherol on Mitochondrial ROS of other neurological manifestations, with minimal pathology outside the nervous system [19]. This indicates that the brain may be uniquely sensitive to ␣-tocopherol deficiency. We examined the effects of ␣-tocopherol deficiency on levels of brain neuroprostane and isoprostanes, reported to be sensitive and specific indices of in vivo lipid peroxidation [20], superoxide radical production in vivo using confocal fluorescence imaging, mitochondrial respiratory function, and superoxide generation from isolated mitochondria using electron paramagnetic resonance spectroscopy and correlated these findings with tissue levels of ␣-tocopherol
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