A Deficiency in Respiratory Complex I in Heart Mitochondria from Vitamin A-Deficient Rats Is Counteracted by an Increase in Coenzyme Q (original) (raw)
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An updating of the biochemical function of Coenzyme Q in mitochondria
Molecular Aspects of Medicine, 1994
The apparent K m for coenzyme Q10 in NADH oxidation by coenzyme Q (CoQ)-extracted beef heart mitochondria is close to their CoQ content, whereas both succinate and glycerol-3-phosphate oxidation (the latter measured in hamster brown adipose tissue mitochondria) are almost saturated at physiological CoQ concentration. Attempts to enhance NADH oxidation rate by excess CoQ incorporation in vitro were only partially successful: the reason is in the limited amount of CoQ10 that can be incorporated in monomeric form, as shown by lack of fluorescence quenching of membrane fluorescent probes; at difference with CoQl0, CoQ5 quenches probe fluorescence and likewise enhances NADH oxidation rate above normal. Attempts to enhance the CoQ content in perfused rat liver and in isolated hepatocytes failed to show uptake in the purified mitochondrial fraction. Nevertheless CoQ cellular uptake is able to protect mitochondrial activities. Incubation of hepatocytes with adriamycin induces loss of respiration and mitochondriai potential measured in whole cells by flow cytometry using rhodamine 123 as a probe: concomitant incubation with CoQt0 completely protects both respiration and potential. An experimental study of aging in the rat has shown some decrease of mitochondrial CoQ content in heart, and less in liver and skeletal muscle. In spite of the little change observed, it is reasoned that CoQ administration may be beneficial in the elderly, owing to the increased demand for antioxidants.
Coenzyme Q and mitochondrial disease
Developmental disabilities research reviews, 2010
Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ(10) supplementation. CoQ(10) deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ(10) deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease ...
Mitochondrial Production of Oxygen Radical Species and the Role of Coenzyme Q as an Antioxidant
Experimental Biology and Medicine, 2003
The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), which is considered as the pathogenic agent of many diseases and of aging. We have investigated the role of complex I in superoxide radical production and found by the combined use of specific inhibitors of complex I that the one-electron donor to oxygen in the complex is a redox center located prior to the sites where three different types of Coenzyme Q (CoQ) competitors bind, to be identified with an Fe–S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain Coenzyme Q analogs enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analog, idebenone, is particularly effective, raising doubts on its safety as a drug. Cells counteract oxidative stress by antioxidants. CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells f...
Archives of biochemistry and …, 1997
Coenzyme Q (ubiquinone, CoQ) 2 plays an essential role in the mitochondrial respiratory chain of all animal We have undertaken a study of the role of coenzyme and plant cells (1). It has been established that CoQ Q (CoQ) in glycerol-3-phosphate oxidation in mitobehaves kinetically as a mobile homogeneous pool chondrial membranes from hamster brown adipose which carries electrons between flavoproteins (Comtissue, using either quinone homologs, as CoQ 1 and plex I and II and other dehydrogenases) and the bc 1 CoQ 2 , or the analogs duroquinone and decylubiquinone as artificial electron acceptors. We have found complex (Complex III) in the inner mitochondrial memthat the most suitable electron acceptor for glycerol-brane (2). The interactions of the CoQ pool with differ-3-phosphate:CoQ reductase activity in situ in the mient respiratory enzymes have been extensively retochondrial membrane is the homolog CoQ 1 yielding viewed (3-7). the highest rate of enzyme activity (225 { 41 nmolr In the past years there has been an increase of medimin 01 rmg 01 protein). With all acceptors tested the cal interest on pathological states associated with coenquinone reduction rates were completely insensitive zyme Q (CoQ) deficiency and the possible therapeutic to Complex III inhibitors, indicating that all aceffects of CoQ supplementation (8, 9). The demonstraceptors were easily accessible to the quinone-binding tion that NADH oxidation, but not succinate oxidation, site of the dehydrogenase preferentially with respect in beef heart mitochondria is not saturating for maxito the endogenous CoQ pool, in such a way that Commal respiratory activity (10) has deep implications on plex III was kept in the oxidized state. We have also the effects of an eventual CoQ deficiency in mitochonexperimentally investigated the saturation kinetics dria (11). Little knowledge, however, exists on the satuof endogenous CoQ (1.35 nmol/mg protein of a mixture ration kinetics of CoQ in other respiratory enzymes. of 70% CoQ 9 and 30% CoQ 10) by stepwise pentane ex-Such a knowledge is deeply required in view of the traction of brown adipose tissue mitochondria and above-mentioned considerations. found a K m of the integrated activity of glycerol-3-The most simple branch of the mitochondrial respiraphosphate cytochrome c reductase for endogenous tory chain connected with the CoQ pool is glycerol-3-CoQ of 0.22 nmol/mg protein, indicating that glycerolphosphate dehydrogenase. This flavin-dependent dehy-3-phosphate-supported respiration is over 80% of V max drogenase is tightly bound to the outer surface of the with respect to the CoQ pool. A similar K m of 0.19 nmol inner mitochondrial membrane and the donor sub-CoQ/mg protein was found in glycerol-3-phosphate strate does not need to cross the inner mitochondrial cytochrome c reductase in cockroach flight muscle membrane to be oxidized. The content of this enzyme mitochondria.
Mitochondrial Complex I: Structural and Functional Aspects
… et Biophysica Acta (BBA …, 2006
This review examines two aspects of the structure and function of mitochondrial Complex I (NADH Coenzyme Q oxidoreductase) that have become matter of recent debate.The supramolecular organization of Complex I and its structural relation with the remainder of the respiratory chain are uncertain. Although the random diffusion model [C.R. Hackenbrock, B. Chazotte, S.S. Gupte, The random collision model and a critical assessment of diffusion and collision in mitochondrial electron transport, J. Bioenerg. Biomembranes 18 (1986) 331-368] has been widely accepted, recent evidence suggests the presence of supramolecular aggregates. In particular, evidence for a Complex I-Complex III supercomplex stems from both structural and kinetic studies. Electron transfer in the supercomplex may occur by electron channelling through bound Coenzyme Q in equilibrium with the pool in the membrane lipids. The amount and nature of the lipids modify the aggregation state and there is evidence that lipid peroxidation induces supercomplex disaggregation. Another important aspect in Complex I is its capacity to reduce oxygen with formation of superoxide anion. The site of escape of the single electron is debated and either FMN, iron-sulphur clusters, and ubisemiquinone have been suggested. The finding in our laboratory that two classes of hydrophobic inhibitors have opposite effects on superoxide production favours an iron-sulphur cluster (presumably N2) is the direct oxygen reductant.The implications in human pathology of better knowledge on these aspects of Complex I structure and function are briefly discussed.
The mitochondrial production of oxygen radical species in relation to pathology and aging
The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), which is considered as the pathogenic agent of many diseases and of aging. We have investigated the role of complex I in superoxide radical production and found by the combined use of specific inhibitors of complex I that the one-electron donor to oxygen in the complex is a redox center located prior to the sites where three different types of Coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain Coenzyme Q analogs enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analog, idebenone, is particularly effective, raising doubts on its safety as a drug. Cells counteract oxidative stress by antioxidants. CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems, likewise, they are overexpressed under oxidative stress conditions.
The specificity of mitochondrial complex I for ubiquinones
Biochemical Journal, 1996
We report the first detailed study on the ubiquinone (coenzyme Q; abbreviated to Q) analogue specificity of mitochondrial complex I, NADH: Q reductase, in intact submitochondrial particles. The enzymic function of complex I has been investigated using a series of analogues of Q as electron acceptor substrates for both electron transport activity and the associated generation of membrane potential.
Biochemistry (Moscow), 2011
NADH:ubiquinone oxidoreductase (complex I) is the most complex component of the mitochondrial respi ratory chain. The major function of the enzyme is oxida tion of the intramitochondrial NADH by ubiquinone (finally by oxygen) thus maintaining the steady state NADH/NAD + ratio, which determines intensity of aero bic oxidative metabolism. Mammalian, yeast, plant, and prokaryotic complex I (NDH 1 homolog) catalyze NADH:quinone oxidoreduction coupled with vectorial proton translocation, thus building up ∆μ Н + needed for ATP synthesis. Mammalian complex I (bovine heart) is composed of 45 different subunits (total molecular mass