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Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate.

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Presentation on theme: "Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate."— Presentation transcript:

1 Quinone for RC deficiency treatment

2 Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate O2O2 CV NADH ADP ATP H2OH2O inner membrane intermembrane space matrix

3 Ubiquinone Quinone biosynthesis pathway mevalonate isopentenyl-PPdimethylallyl-PP tyrosine 4-OH-benzoate chorismate prephenate 4-OH-phenylpyruvate polyprenyl-PP polyprenyl-OH-benzoate geranyl-PP transtransfarnesyl-PP geranylgeranyl-PP C C C C C C H H H H OH O P O O-O- O-O- OP O O O-O- CH 2 CHCH 2 CH 3 n C

4 Ubiquinone CoQ 6 Quinone biosynthesis pathway mevalonate isopentenyl-PPdimethylallyl-PP tyrosine 4-OH-benzoate chorismate prephenate 4-OH-phenylpyruvate hexaprenyl-PP geranyl-PP transtransfarnesyl-PP geranylgeranyl-PP C C C C C C H H H H OH O P O O-O- O-O- OP O O O-O- CH 2 CHCH 2 CH 3 6 C COQ7 COQ4 COQ3 COQ6 COQ5 COQ1 COQ2 COQ8 COQ9 COQ10 S. cerevisiae hexaprenyl-OH-benzoate

5 mevalonate isopentenyl-PPdimethylallyl-PP tyrosine 4-OH-benzoate chorismate prephenate 4-OH-phenylpyruvate decaprenyl-PP decaprenyl-OH-benzoate Ubiquinone CoQ 10 geranyl-PP transtransfarnesyl-PP geranylgeranyl-PP C C C C C C H H H H OH O P O O-O- O-O- OP O O O-O- CH 2 CHCH 2 CH 3 10 C COQ7 COQ4 COQ3 COQ6 COQ5 FPP PDSS1+PDSS2 COQ2 COQ8 COQ9 COQ10 ADCK1 ADCK2 ADCK4 ADCK5 Quinone biosynthesis pathway H. sapiens

6 mevalonate isopentenyl-PPdimethylallyl-PP tyrosine 4-OH-benzoate decaprenyl-PP decaprenyl-OH-benzoate CoQ 10 geranyl-PP transtransfarnesyl-PP geranylgeranyl-PP Genes for ubiquinone deficiencies COQ8/CABC1 E551K R213W G272V G272D c.[ insG] Ataxia Seizures Mild mental retardation COQ2 Neurological distress Liver failure Nephrotic syndrome N401fsX415 PDSS1 Deafness Mental retardation Obesity D308E PDSS2 Deafness Nephrotic syndrome Mental retardation Myopathy Ataxia Cataract… S382L

7 After 14 mths of treatment: Can stand and walk unaided Head control Can take, hold and give back Fixes and smiles Diseappeared Does not want to go to bed at night Before treatment Wheel-chair bound Neck muscle weakness Could not grasp Reduced visual contact Drooling, cataract Needed a nap in afternoon Treatment of ubiquinone deficiency Patient with PDSS2 mutation

8 Treatment of ubiquinone deficiency Patient with COQ8 mutation P1:cerebellar ataxia seizures trunk hypotonia oral CoQ 10 treatment (5-10 mg/kg/day) no clinical benefits C C C C C C O O CH 2 CH C CH 3 CH 2 x 10 CH 3 O CH 3 H Coenzyme Q10 Ubiquinone CH 2 CH 2 OH CH 2 C C C C C C O O CH 3 O CH 3 Idebenone oral idebenone treatment (10 mg/kg/day) failed to improve his condition and worsened the course of the disease

9 Patients: clinical improvement in some cases Patients mitochondria: rapid activation of CII+III activity by exogenous quinone Yeast coq mutants: rescue of growth by quinone supplementation The respiratory chain deficiency is rapidly corrected by exogenous quinone Insufficient uptake of CoQ 10 across the blood-brain barrier in patients Treatment of ubiquinone deficiency

10 Friedreich ataxia Progressive cerebellar ataxia Lack of deep tendon reflexesHypertrophic cardiomyopathy Diabetes mellitus (10%) Carbohydrate intolerance (20%) Autosomal recessive Frequence: 1/50,000 Gene localisation: 9q13-q21 (Chamberlain et al, Nature 1988) The gene encodes a 210 AA protein, frataxin ( Campuzano et al, Science 1996) GAA repeat expansion in the first intron

11 Cys Ala Fe2+ Isu1/2 NADH from R. Lill Nfs1 Arh1Yah1 Isa1/2 Nfu1 Yfh1 SS SS SS mitochondrial Fe-S protein Mrs3/4 Grx5 Ssq1Jac1Mge1 extramitochondrial Fe-S protein CIA machinery Cdf1, Nbp5, Nar1 cytosol mitochondria Iron-sulfur synthesis in yeast Yeast Yfh1 = Human frataxin

12 Iron-sulfur proteins targeted in Friedreich ataxia UQ C I CII CIII CIV c Succinate NADH O2O2 ISp ISp : iron-sulfur protein Inner membrane Outer membrane ISp Aconitase Krebs cycle ISp Aconitase Matrix Cytosol ISp

13 Fe 2+ O2O2 ISPs Frataxin Respiratory chain deficiency Triplet expansion

14 Antioxidants Chelators ? Fe 2+ O2O2 ISPs Frataxin

15 Idebenone 6-(10-hydroxydecyl)-2,3-dimethoxy- 5-methyl-1,4-benzoquinone C 19 H 29 O 5 MW: 338 CH 2 CH 2 OH CH 2 C C C C C C O O CH 3 O CH 3 Quinone ringSide chain

16 The effect of idebenone oral supplementation (6 months) on the left-ventricular mass index in 52 FRDA patients Increased >20% 85% 15% 39% 46% Stable or decreased <20% Decreased >-20%

17 What about the neurological condition in FRDA patients treated by idebenone ? Patients, families and/or clinicians often report: - Decreased fatigability - Improvement of delicate movements (handwriting,drawing, control of the wheelchair commands) - Better voice (use of the phone) - Decreased swallowing difficulties Yet ataxia and deep tendon reflexes did not change significantly after 1 year treatment

18 TRIALING IDEBENONE IN FRDA 3 patients / 6 m treat. / decreased cardiac hypertrophy / no improvement of ataxia (1998 Hôpital Necker, Paris, France; The Lancet) 8 patients / 1 y treat. / scores of ARS scale improved in all patients (2001 Hospital Sant Joan de Déu, Barcelona, Spain; Arthur et al. Euromit 5) 9 patients (5 treated) / 6 weeks treat. / neither improvement of cardiac hypertrophy nor of neurological condition (2001 St Josef Hospital, Bochum, Germany; Schöls et al. Neurosc. Lett) 11 patients / 1 y treat. / decreased heart hypertrophy in all patients / no improvement of ataxia (2001 Hôpital Sainte-Justine, Montréal, Canada; Emond et al, WebSite) 29 patients (15 treated) / 6 m treat. / reduced heart hypertrophy / no improvement of the ARS scale (2001 Milano, Italy; for ataxia (Mariotti et al. J Neurol.) 38 patients / 6 m treat. / decreased cardiac hypertrophy (50% of the patients) / no improvement of ataxia (2002 Hôpital Necker, Paris, France; Heart; Free Rad. Res.) 50 patients / 1 y treat. / decreased cardiac hypertrophy / no improvement of ataxia (2002 The French official trial; Hôpital de la Salpetrière et Hôpital Necker, Paris, France)

19 Quinone for RC deficiency treatment Restoring electron flow replacement therapy in ubiquinone biosynthesis defects ubiquinone (CoQ 10 ) Increasing antioxidant defenses evidence of mitochondrial oxidative stress ubiquinone biosynthesis defects idebenone


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