ubiquinone and Genetic-Diseases--Inborn

Inherited defects of the mitochondrial succinate dehydrogenase (SDH) in humans are associated with striking variable clinical presentations ranging from early-onset devastating encephalomyopathy to tumour susceptibility in adulthood, or optic atrophy in the elderly. Although different genes encoding the four subunits of the SDH have been found mutated in association with these different phenotypes, we propose that the wide clinical spectrum actually originates from the specific roles of the SDH in the respiratory chain and the mitochondria. In particular, beside its function in the Krebs cycle and the respiratory chain, the specific redox properties of the enzyme could confer to the SDH a specific function in superoxide handling.

Topics: Adenosine Triphosphate; Animals; Caenorhabditis elegans; Citric Acid Cycle; Electron Transport; Genetic Diseases, Inborn; Humans; Mutation; Paraganglioma; Phenotype; Succinate Dehydrogenase; Ubiquinone

Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

Topics: Adolescent; Adult; Benzoquinones; Brain; Cells, Cultured; Child; Child, Preschool; Female; Fibroblasts; Gene Expression Regulation; Genetic Diseases, Inborn; Humans; Male; Mitochondrial Diseases; Oxidative Stress; Oximes; Tomography, Emission-Computed, Single-Photon; Ubiquinone

Several mutations in the mitochondrially encoded cytochrome b have been reported in patients. To characterize their effect, we introduced six "human" mutations, namely G33S, S152P, G252D, Y279C, G291D, and Delta252-259 in the highly similar yeast cytochrome b. G252D showed wild type behavior in standard conditions. However, Asp-252 may interfere with structural lipid and, in consequence, destabilize the enzyme assembly, which could explain the pathogenicity of the mutation. The mutations G33S, S152P, G291D, and Delta252-259 were clearly pathogenic. They caused a severe decrease of the respiratory function and altered the assembly of the iron-sulfur protein in the bc(1) complex, as observed by immunodetection. Suppressor mutations that partially restored the respiratory function impaired by S152P or G291D were found in or close to the hinge region of the iron-sulfur protein, suggesting that this region may play a role in the stable binding of the subunit to the bc(1) complex. Y279C caused a significant decrease of the bc(1) function and perturbed the quinol binding. The EPR spectra showed an altered signal, indicative of a lower occupancy of the Q(o) site. The effect of human mutation of residue 279 was confirmed by another change, Y279A, which had a more severe effect on Q(o) site properties. Thus by using yeast as a model system, we identified the molecular basis of the respiratory defect caused by the disease mutations in cytochrome b.

Topics: Aspartic Acid; Binding Sites; Blotting, Western; Cytochromes b; Cytochromes c; Cytochromes c1; Electron Spin Resonance Spectroscopy; Electron Transport Complex III; Fungal Proteins; Genetic Diseases, Inborn; Humans; Immunoblotting; Intracellular Membranes; Iron-Sulfur Proteins; Kinetics; Lipids; Magnetics; Mitochondria; Models, Molecular; Mutation; Saccharomyces cerevisiae Proteins; Spectrophotometry; Suppression, Genetic; Temperature; Ubiquinone