The antioxidant role of coenzyme Q
Introduction
Oxygen present in the atmosphere is the basis of our life on earth. Paradoxical is the fact that it is a very toxic substance under a number of conditions. Derivatives, such as hydroxyl and superoxide radicals, hydrogen peroxide and singlet oxygen may be formed and are called reactive oxygen species (ROS). These compounds appear not only in diseases but also under normal physiological conditions and interact with basic tissue components with consequences of disturbed function. Various types of antioxidant defense systems are, however, available in all organisms for limitation and elimination of these unwanted species.
Increased levels of free radicals are counteracted by antioxidants, but low concentrations of these compounds participate in redox signaling and by regulating gene expression they influence among others the activation and synthesis of antioxidants and other enzymes (Sen and Packer, 1996). Cellular effects elicited by minor amounts of ROS products, such as the generation of growth factors, production of hormones and modulation of tyrosine phosphatase are of great importance in cell cycle regulation, proliferation, differentiation and survival (Martindale and Holbrook, 2002). These radicals also participate in the regulation of immune response through the T cells by suppressing autoreactivity and development of arthritis (Gelderman et al., 2006).
Section snippets
ROS formation
In a number of enzymatic processes oxygen is reduced by one electron transfer to the superoxide radical , hydrogen peroxide (H2O2) and hydroxyl radical (OH) (Cadenas et al., 1992). The enzymes which belong to this group are the monoamine oxidase in mitochondrial outer membranes, acyl-CoA oxidase of peroxisomes, xanthine oxidase, microsomal NADH-cytochrome b5 and cytochrome-P450 reductases and the NADPH oxidase in neutrophils. Mitochondrial electron transport is accounted for two-thirds of
Lipid, protein and DNA oxidation
Excess of free radicals affects the basic cellular constituents such as lipids, proteins and DNA and the damage caused is known as oxidative stress. Lipid peroxidation is a process studied in great detail and the mechanism is well characterized (Ernster, 1993). During the first phase, called initiation, an abstraction of a hydrogen atom from a methylene group of a fatty acid occurs presupposing that it has several double bonds (Fig. 1). This gives a carbon-centered alkyl radical (L) and
Distribution of CoQ
Biosynthesis of CoQ occurs in all tissues and cells in the animal organism and the lipid is present in all membranes (Turunen et al., 2004). The amount is specific for the membrane type which is apparent in comparison with the distribution of other membrane lipids (Table 1). The CoQ amount related to dolichol, cholesterol or α-tocopherol amounts is highly variable and is a consequence of the functional specialization associated with the individual membranes. From the point of view of
Antioxidant action of CoQ
There are four major groups of naturally occurring lipid soluble antioxidants, carotenoids, tocopherols, estrogens and coenzyme Q. The individual components in the groups vary greatly concerning distribution and effectiveness, e.g., in the group of vitamin E eight major compounds are operating, α-, β-, γ- and δ-tocopherols and -tocotrienols but in humans only α-tocopherol is effective as antioxidant. The liver contains a transfer protein that is specific for α-tocopherol and this compound is
Enzymatic reduction
The amount of CoQ varies greatly in different tissues and subcellular organelles. In most cases the major part of the lipid is found in a reduced form. In spite of the fact that during storage and isolation some autooxidation is expected, in most human autopsy material the proportion of the reduced form is the dominant species (Table 4). Autopsy material is probably not ideal for measurement of the steady state reduction of CoQ, however, the values are comparable with the values obtained on
The antioxidant role in blood
In plasma the CoQ content in very low density, low density and high density lipoproteins is 1.2, 1.0 and 0.1 nmol/mg protein, respectively. The amounts are increased after dietary administration of the lipid to 3.2, 3.5 and 0.3 nmol/mg protein, respectively (Mohr et al., 1992). In all tissues the CoQ content is 6–10 times higher than that of vitamin E but in the blood its amount is only one-tenth of the main blood lipid soluble antioxidant, vitamin E. However, the very efficient reductive
CoQ as prooxidant
It is known that electron leakage occurs during mitochondrial respiration leading to superoxide radicals and H2O2. Findings such as that respiration gives ubisemiquinone which reacts with oxygen, that antimycin increase electron leakage and that extraction of CoQ from mitochondria inhibits H2O2 production, leads to a plausible assumption that CoQ can promote oxidation in mitochondria. Part of the ubisemiquinone is produced at the outer section of the membrane, bordering the aqueous phase. This
Stability and oxidative stress
There are several indications that under various pathological conditions CoQ in membranes is structurally modified and subjected to breakdown. The importance of these modifications is that the products may act as signaling molecules and influence a number of metabolic and synthetic pathways. The high degree of reduction of this lipid is not only a functional requirement but it is also a necessity for protection against oxidative damages (Forsmark-Andree et al., 1997). Submitochondrial particles
Induction of biosynthesis
Lowered CoQ content in tissues may appear as a primary deficiency for genetic reasons, caused by aging or by damage of the biosynthetic system in diseases and toxic injury. The decrease may be extensive or mild and probably much more common than assumed today. In the case of cholesterol, the liver produces the lipid to supply other organs and one-third of the required daily amount is taken up from the diet. Consequently, cholesterol level in the blood is a mirror and diagnostic marker for the
Conclusions
The high efficiency of CoQ as a lipid soluble antioxidant is established because of its localization, effective reactivation and relatively high concentration. Additionally, it appears both to inhibit the initiation part and interfere with the propagation step of lipid and protein oxidation, a property not apparent in the case of other antioxidants. All tissues and cells are capable of synthesis of this lipid to such an extent that ensures sufficient local concentration without redistribution
Acknowledgements
The authors work is supported by the Swedish Research Council, the Family Erling-Persson Foundation and the European Community (CT-2004-005151).
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