Original ContributionsVitamin E regulates mitochondrial hydrogen peroxide generation
Introduction
Since vitamin E was discovered over 70 years ago [1], a number of species-dependent deficiency symptoms of vitamin E have been reported [2], [3]. The essentiality of vitamin E for humans was established in the late 1960s. The recognition was largely derived from clinical investigations involving premature infants [3], [4]. Studies of children and adults with specific causes of fat malabsorption and patients with familial isolated vitamin E deficiency syndrome have conclusively shown that neurologic dysfunction is associated with vitamin E deficiency and that vitamin E is an essential nutrient necessary for the optimal development and maintenance of human nervous system integrity and function [5], [6], [7]. Recent reports on the benefit of vitamin E supplements in reducing the risk of cardiovascular disease, Alzheimer’s disease, and other degenerative disorders [8], [9], [10], [11], [12], [13], [14] have raised public interest in the vitamin to a new height. However, the mechanism by which vitamin E can delay or protect against the development of tissue degeneration remains to be delineated.
Mitochondria, the intracellular organelle that produce adenosine triphosphate, constitute the greatest source of steady state oxidants. The mitochondrial electron transport system consumes more than 85% of all the oxygen used by the cells, and it is estimated that between 1 and 5% of the oxygen consumed by mitochondria is converted to superoxide, hydrogen peroxide, and other ROS under normal physiological conditions [15], [16], [17]. Proximal to a large flux of ROS, mitochondria DNA is particularly susceptible to oxidative damage and mutation because it lacks protective histones and an effective repair system [18], [19], [20]. Mitochondrial DNA, for example, has a 16-fold higher oxidized base than nuclear DNA [21], and the accumulation of mitochondrial DNA damage products increases with age [22], [23]. In addition to oxidative damage to lipid and protein in mitochondria, many studies have found that increased oxidative lesions, deletions, point mutations, and aberrant forms in mitochondrial DNA of postmitotic tissues on aging and have suggested that mitochondrial respiratory chain defects and DNA mutations are two key contributors to human aging and neurodegenerative diseases [24], [25], [26], [27], [28], [29], [30].
As the major producer of ROS in the cell, it is important that mitochondrion has the highest concentration of vitamin E and that most of it is in the inner membrane [31]. It has long been recognized that the disruption of mitochondrial ultrastructure is one of the earliest pathologic events observed in the skeletal muscle of vitamin E–deficient animals [32]. Also, de novo synthesis of xanthine oxidase, which serves as a source of superoxide, is markedly increased in the skeletal muscle of vitamin E–deficient rabbits [33]. This activity has also been shown to be significantly higher in the liver of vitamin E–deficient rats [34]. These findings suggest an increased generation of superoxide during vitamin E deficiency and a direct involvement of excessive ROS as a cause of developing vitamin E–deficient syndromes. The studies reported herein sought to determine whether vitamin E has a direct functional effect over the production of ROS in mitochondria. Results clearly showed that dietary vitamin E markedly reduces hydrogen peroxide production in the mitochondria of liver and skeletal muscle derived from two rodent species and that this suppression was closely related to the vitamin E concentration of the diet. The results obtained from this research indicate that vitamin E regulates mitochondrial generation of ROS. This unique and direct function of vitamin E may in turn modulate signal transduction pathways and other redox-sensitive biologic modifiers, and thereby prevent or delay the development of degenerative diseases.
Section snippets
Chemicals and reagents
Mono- and dibasic sodium phosphate and 30% hydrogen peroxide were purchased from Fisher Scientific (Cincinnati, OH, USA); high-performance liquid chromatography-grade methanol, hexane, and water were purchased from EM Science (Gibbstown, NJ, USA); 95% ethanol was obtained from Midwest Grain Products (Pekin, IL, USA; isobutyl alcohol was obtained from Mallinckroft Chemist (St. Louis, MO, USA); 1,1,3,3-tetramethoxypropane, β-nicotinamide adenine dinucleotide (reduced form), 2-thiobarbituric acid,
Results
After 15 weeks on the vitamin E–deficient diet, the status of vitamin E in this group of mice was compared with corresponding controls that received the same diet supplemented with 50 IU vitamin E/kg diet. Figure 1 shows that in the deficient group, the levels of vitamin E were markedly lower, whereas TBA reactant values were significantly (p < .05) higher in skeletal muscle. Plasma pyruvate kinase activity, a sensitive indicator of myodegeneration [3], [36], was significantly elevated in the
Discussion
Results from Fig. 2 clearly show that regardless of the presence or absence of added superoxide dismutase to the incubations, there was no effect in the production of hydrogen peroxide from mitochondria isolated from mouse liver and skeletal muscle. This suggests that mitochondrial superoxide dismutase provides sufficient activity to convert superoxide generated to hydrogen peroxide rapidly; is also suggests that in situ superoxide, rather than hydrogen peroxide, was the original ROS generated.
Acknowledgements
This work was supported in parts by the University of Kentucky Agricultural Experiment Station.
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