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Idebenone AND Electron transport chain

Yan Burelle, Chantal Bemeur, Marie-Eve Rivard, Julie Thompson Legault, Gabrielle Boucher, Charles Morin, Lise Coderre, Christine Des Rosiers
Mutations in LRPPRC are responsible for the French Canadian variant of Leigh Syndrome (LSFC), a severe disorder characterized biochemically by a tissue-specific deficiency of cytochrome c oxidase (COX) and clinically by the occurrence of severe and deadly acidotic crises. Factors that precipitate these crises remain unclear. To better understand the physiopathology and identify potential treatments, we performed a comprehensive analysis of mitochondrial function in LSFC and control fibroblasts. Furthermore, we have used this cell-based model to screen for conditions that promote premature cell death in LSFC cells and test the protective effect of ten interventions targeting well-defined aspects of mitochondrial function...
2015: PloS One
Sausan Jaber, Brian M Polster
UNLABELLED: Ubiquinone, commonly called coenzyme Q10 (CoQ), is a lipophilic electron carrier and endogenous antioxidant found in all cellular membranes. In the mitochondrial inner membrane it transfers electrons to complex III of the electron transport chain. The short chain CoQ analogue idebenone is in clinical trials for a number of diseases that exhibit a mitochondrial etiology. Nevertheless, evidence that idebenone ameliorates neurological symptoms in human disease is inconsistent...
April 2015: Journal of Bioenergetics and Biomembranes
Ying Wang, Siegfried Hekimi
Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ...
December 1, 2013: Human Molecular Genetics
David M Fash, Omar M Khdour, Sunil J Sahdeo, Ruth Goldschmidt, Jennifer Jaruvangsanti, Sriloy Dey, Pablo M Arce, Valérie C Collin, Gino A Cortopassi, Sidney M Hecht
The effect of the alkyl side chain length of coenzyme Q10 on mitochondrial respiratory chain function has been investigated by the use of synthetic ubiquinone derivatives. Three analogues (3, 4 and 6) were identified that exhibited significantly improved effects on mitochondrial oxygen consumption and mitochondrial membrane potential, and also conferred significant cytoprotection on cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. The analogues also exhibited lesser inhibition of the electron transport chain than idebenone...
April 15, 2013: Bioorganic & Medicinal Chemistry
Douglas S Kerr
Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria)...
April 2013: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Ruth Goldschmidt, Pablo M Arce, Omar M Khdour, Valérie C Collin, Sriloy Dey, Jennifer Jaruvangsanti, David M Fash, Sidney M Hecht
Two new aza analogues of the neuroprotective agent idebenone have been synthesized and characterized. Their antioxidant activity, and ability to augment ATP levels have been evaluated in several different cell lines having suboptimal mitochondrial function. Both compounds were found to be good ROS scavengers, and to protect the cells from oxidative stress induced by glutathione depletion. The compounds were more effective than idebenone in neurodegenerative disease cells. These novel pyrimidinol derivatives were also shown to augment ATP levels in coenzyme Q(10)-deficient human lymphocytes...
February 15, 2013: Bioorganic & Medicinal Chemistry
Fabrice D Heitz, Michael Erb, Corinne Anklin, Dimitri Robay, Vincent Pernet, Nuri Gueven
Leber's hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON...
2012: PloS One
Pablo M Arce, Ruth Goldschmidt, Omar M Khdour, Manikandadas M Madathil, Jennifer Jaruvangsanti, Sriloy Dey, David M Fash, Jeffrey S Armstrong, Sidney M Hecht
Selected pyridinol analogues of the experimental neuroprotective drug idebenone have been synthesized and evaluated as antioxidants capable of preserving mitochondrial function. The compounds, having a different redox core but the same side chain as idebenone, exhibited a range of potencies, reflecting differences in their structures. The results obtained provide guidance in the design of such analogues with improved properties. Analogues were identified that have significantly improved antioxidant activity compared with idebenone in cultured lymphocytes, and which exhibit lesser inhibition of the electron transport chain...
September 1, 2012: Bioorganic & Medicinal Chemistry
Michael Erb, Barbara Hoffmann-Enger, Holger Deppe, Michael Soeberdt, Roman H Haefeli, Christian Rummey, Achim Feurer, Nuri Gueven
Short-chain quinones have been investigated as therapeutic molecules due to their ability to modulate cellular redox reactions, mitochondrial electron transfer and oxidative stress, which are pathologically altered in many mitochondrial and neuromuscular disorders. Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP. Although this energy rescue activity is highly interesting for the therapy of disorders associated with complex I dysfunction, no structure-activity-relationship has been reported for short-chain quinones so far...
2012: PloS One
Natalie Watzke, Kerstin Diekert, Petr Obrdlik
Transport of protons and solutes across mitochondrial membranes is essential for many physiological processes. However, neither the proton-pumping respiratory chain complexes nor the mitochondrial secondary active solute transport proteins have been characterized electrophysiologically in their native environment. In this study, solid-supported membrane (SSM) technology was applied for electrical measurements of respiratory chain complexes CI, CII, CIII, and CIV, the F(O)F(1)-ATPase/synthase (CV), and the adenine nucleotide translocase (ANT) in inner membranes of pig heart mitochondria...
December 7, 2010: Biochemistry
Claudia Becker, Katharine Bray-French, Juergen Drewe
IMPORTANCE OF THE FIELD: Idebenone is a synthetic short chain benzoquinone that acts as an electron carrier in the mitochondrial electron transport chain, thereby, facilitating the production of ATP. In addition, idebenone is an antioxidant and can inhibit lipid peroxidation and may protect cell membranes and mitochondria from oxidative damage. High dose idebenone (Catena(®)) is approved in Canada for the symptomatic treatment of Friedreich's ataxia and is currently under clinical investigation for use in a number of mitochondrial and neuromuscular diseases...
November 2010: Expert Opinion on Drug Metabolism & Toxicology
Douglas S Kerr
While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy...
March 2010: Molecular Genetics and Metabolism
M Mancuso, D Orsucci, L Volpi, V Calsolaro, G Siciliano
Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders...
January 2010: Current Drug Targets
Romana Fato, Christian Bergamini, Serena Leoni, Giorgio Lenaz
Mitochondrial reactive oxygen species (ROS) are mainly produced by the respiratory chain enzymes. The sites for ROS production in mitochondrial respiratory chain are normally ascribed to the activity of Complex I and III. The presence of specific inhibitors modulates reactive oxygen species production in Complex I: inhibitors such as rotenone induce a strong ROS increase, while inhibitors such as stigmatellin prevent it. We have investigated the effect of hydrophilic quinones on Complex I ROS production in presence of different inhibitors...
2008: BioFactors
H Rauchová, Z Drahota, C Bergamini, R Fato, G Lenaz
Idebenone (IDE), a synthetic analog of coenzyme Q, strongly activates glycerol phosphate (GP) oxidation in brown adipose tissue mitochondria. GP oxidase, GP cytochrome c oxidoreductase and GP dehydrogenase activities were all significantly stimulated by 13 muM IDE. Substituted derivatives of IDE acetyl- and methoxyidebenone had similar activating effects. When succinate was used as substrate, no activation by IDE could be observed. The activation effect of IDE could be explained as release of the inhibition of glycerol phosphate dehydrogenase by endogenous free fatty acids...
April 2008: Journal of Bioenergetics and Biomembranes
J M Cooper, A H V Schapira
Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis...
2003: BioFactors
Maria Luisa Genova, Milena Merlo Pich, Annalisa Biondi, Andrea Bernacchia, Anna Falasca, Carla Bovina, Gabriella Formiggini, Giovanna Parenti Castelli, Giorgio Lenaz
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...
May 2003: Experimental Biology and Medicine
Vanna Geromel, Niklas Darin, Dominique Chrétien, Paule Bénit, Pascale DeLonlay, Agnès Rötig, Arnold Munnich, Pierre Rustin
While there have been major advances in both the identification of the molecular basis and our understanding of mitochondrial pathology, the clinical management of patients with mitochondrial respiratory chain disease is still essentially supportive. Quinones are the only pharmacological agents that have proven some efficacy when, and only when, given to patients presenting with quite specific respiratory chain defects. In this article, after a short presentation of the coenzyme Q(10) molecule, its origin and distribution in human body, we summarize our present knowledge on its several physiological functions...
September 2002: Molecular Genetics and Metabolism
Giorgio Lenaz, Carla Bovina, Marilena D'Aurelio, Romana Fato, Gabriella Formiggini, Maria Luisa Genova, Giovanni Giuliano, Milena Merlo Pich, Ugo Paolucci, Giovanna Parenti Castelli, Barbara Ventura
The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), 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 combined use of specific inhibitors of Complex I that the one-electron donor in the Complex to oxygen 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...
April 2002: Annals of the New York Academy of Sciences
M L Genova, B Ventura, G Giuliano, C Bovina, G Formiggini, G Parenti Castelli, G Lenaz
The mitochondrial respiratory chain is a powerful source of reactive oxygen species, considered as the pathogenic agent of many diseases and of aging. We have investigated the role of Complex I in superoxide radical production in bovine heart submitochondrial particles and found, by combined use of specific inhibitors of Complex I and by Coenzyme Q (CoQ) extraction from the particles, that the one-electron donor in the Complex to oxygen is a redox center located prior to the binding sites of three different types of CoQ antagonists, to be identified with a Fe-S cluster, most probably N2 on the basis of several known properties of this cluster...
September 21, 2001: FEBS Letters
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