Biochemical functions of coenzyme Q10
Coenzyme Q is well defined as a crucial component of the oxidative phosphorylation process in mitochondria which converts the energy in carbohydrates and fatty acids into ATP to drive cellular machinery and synthesis. New roles for coenzyme Q in other cellular functions are only becoming recognized.
The new aspects have developed from the recognition that coenzyme Q can undergo oxidation/reduction reactions in other cell membranes such as lysosomes. Golgi or plasma membranes. In mitochondria and lysosomes, coenzyme Q undergoes reduction/oxidation cycles during which it transfers protons across the membrane to form a proton gradient. The presence of high concentrations of quinol in all membranes provides a basis for antioxidant action either by direct reaction with radicals or by regeneration of tocopherol and ascorbate. Evidence for a function in redox control of cell signaling and gene expression is developing from studies on coenzyme Q stimulation of cell growth, inhibition of apoptosis, control of thiol groups, formation of hydrogen peroxide and control of membrane channels. Deficiency of coenzyme Q has been described based on failure of biosynthesis caused by gene mutation, inhibition of biosynthesis by HMG coA reductase inhibitors (statins) or for unknown reasons in ageing and cancer. Correction of deficiency requires supplementation with higher levels of coenzyme Q than are available in the diet.
Coenzyme Q (CoQ) was isolated and characterized by Festenstein et al. in 1955 [1] and it was established in 1957 by Crane et al. [2] that this compound functions as a member of the mitochondrial respiratory chain. Wolf et al. [3]determined its complex structure in 1958. CoQ was found to be an unusual lipid since the redox active benzoquinone ring is connected to a long isoprenoid side chain, requiring specific placements in a biological membrane. At this time only the redox function of this lipid was studied while its function as an antioxidant was investigated mainly during the past 15 years. In the initial period, the concept of CoQ distribution and synthesis was attributed exclusively to the inner mitochondrial membrane. This appeared to be reasonable since the only known function at this time was shuttling electrons from complexes I and II to complex III in the mitochondrial electron transfer system.
During the 1960s the obligatory role of CoQ in the respiratory chain was proven by several facts, such as depletion and reincorporation of the lipid into submitochondrial particles causing inactivation and reactivation of NADH and succinate dehydrogenas activities [4]. In 1975 Mitchell [5] proposed the protonmotive Q cycle, the cyclic electron transfer pathway through complex III involving ubisemiquinone, a proposal generally accepted. The role of CoQ in the mitochondrial respiratory chain and associated oxidative phosphorylation is studied in great details by many investigators and is not discussed here. There are recent and excellent reviews about this subject which are recommended to consult
1.1. The plasma membrane redox system
The plasma membrane of eukaryotic cells contains an NADH oxidase (NOX) that is involved in the transfer of electrons across the membrane (Fig. 1). The name of this enzyme was given in the initial period of studies, when it was believed that the function of the enzyme is the oxidation of the externally added NADH. The NOX protein is not a transmembranous protein but is located at the external surface of the plasma membrane [10]. It has both hydroquinone (or NADH) oxidase and protein-disulfide-thiol interchange activities that have been shown to respond to hormones and growth factors[11], [12]. The NOX protein is not related to the NADPH oxidase found in neutrophils, which is not dependent of CoQ [13]. At the cytosolic surface, a quinone reductase is present that catalyzes the reduction of CoQ in the presence of NADH [14]. This system together with the enzymatic mechanisms discussed in Section 7 are responsible for regeneration of cellular reduced CoQ. The participation of CoQ in the plasma membrane electron transportwas shown by the fact that the NOX activity was inhibited by removal of CoQ with heptane and reconstitution of the activity by CoQ addition [15]. Several terminal electron acceptors have been suggested, such as molecular oxygen, protein disulfides or ascorbyl radicals
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