Prolonged alpha-tocopherol deficiency decreases oxidative stress and unmasks alpha-tocopherol-dependent regulation of mitochondrial function in the brain.
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.
Cuddihy
Sarah L
SL
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ali
Sameh S
SS
Musiek
Erik S
ES
Lucero
Jacinta
J
Kopp
Sarah J
SJ
Morrow
Jason D
JD
Dugan
Laura L
LL
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D018384:Oxidative Stress; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species; D014810:Vitamin E / Q000378:metabolism; D024502:alpha-Tocopherol / Q000378:metabolism
D002352:Carrier Proteins; D017382:Reactive Oxygen Species; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D024502:alpha-Tocopherol