quinone for rc deficiency treatment. ubiquinone function in mitochondrial respiratory chain...
TRANSCRIPT
![Page 1: Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate](https://reader036.vdocument.in/reader036/viewer/2022062511/55162933550346c6758b4a78/html5/thumbnails/1.jpg)
Quinone for RC deficiency treatment
![Page 2: Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate](https://reader036.vdocument.in/reader036/viewer/2022062511/55162933550346c6758b4a78/html5/thumbnails/2.jpg)
Ubiquinone function in mitochondrial respiratory chain
C
C
C
C
C
C
O
O
CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH3
Ubiquinone = Coenzyme Q = CoQ10
UQUQ
C I
CII
CIII
CIV
c
SuccinateO2
CV
NADHADP ATP
H2O
inner membrane
intermembrane space
matrix
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Ubiquinone
Quinone biosynthesis pathwaymevalonate
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
OOH
P
O
O-
O-
OP
O
O
O-
CH2
CH CH2
CH3
nC
C
C
C
C
C
C
O
O
CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH2CH2
CHC
CH3
CH3
![Page 4: Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate](https://reader036.vdocument.in/reader036/viewer/2022062511/55162933550346c6758b4a78/html5/thumbnails/4.jpg)
UbiquinoneCoQ6
Quinone biosynthesis pathwaymevalonate
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
OOH
P
O
O-
O-
OP
O
O
O-
CH2
CH CH2
CH3
6C
COQ7
COQ4COQ3COQ6COQ5
COQ1
COQ2
COQ8COQ9COQ10
S. cerevisiae
hexaprenyl-OH-benzoate
![Page 5: Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate](https://reader036.vdocument.in/reader036/viewer/2022062511/55162933550346c6758b4a78/html5/thumbnails/5.jpg)
mevalonate
isopentenyl-PPdimethylallyl-PP
tyrosine
4-OH-benzoate
chorismate
prephenate
4-OH-phenylpyruvate
decaprenyl-PP
decaprenyl-OH-benzoate
UbiquinoneCoQ10
geranyl-PP
transtransfarnesyl-PP
geranylgeranyl-PP
C
C
C
C
C
C
H
H
H
H
OH
OOH
P
O
O-
O-
OP
O
O
O-
CH2
CH CH2
CH3
10C
COQ7
COQ4
COQ3
COQ6COQ5
FPP
PDSS1+PDSS2
COQ2
COQ8COQ9COQ10ADCK1ADCK2ADCK4ADCK5
Quinone biosynthesis pathway
H. sapiens
![Page 6: Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate](https://reader036.vdocument.in/reader036/viewer/2022062511/55162933550346c6758b4a78/html5/thumbnails/6.jpg)
mevalonate
isopentenyl-PPdimethylallyl-PP
tyrosine
4-OH-benzoate decaprenyl-PP
decaprenyl-OH-benzoate
CoQ10
geranyl-PP
transtransfarnesyl-PP
geranylgeranyl-PP
Genes for ubiquinone deficiencies
COQ8/CABC1
E551KE551K
R213WG272V
G272Dc.[1812-1813insG]
AtaxiaSeizuresMild mental retardation
COQ2Neurological distressLiver failureNephrotic syndrome
N401fsX415N401fsX415
PDSS1
DeafnessMental retardationObesity D308E
D308E
PDSS2
DeafnessNephrotic syndromeMental retardationMyopathyAtaxiaCataract…
S382LS382L
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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
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Treatment of ubiquinone deficiency
Patient with COQ8 mutation
P1: cerebellar ataxiaseizurestrunk hypotonia
oral CoQ10 treatment (5-10 mg/kg/day) no clinical benefits
C
C
C
C
C
C
O
O
CH2
CHC
CH3
CH2
x 10
CH3O
CH3O
CH3
H
Coenzyme Q10Ubiquinone
CH2
CH2CH2
CH2CH2
CH2CH2
CH2OHCH2
CH2
C
C
C
C
C
C
O
O
CH3O
CH3O
CH3
Idebenone
oral idebenone treatment (10 mg/kg/day) failed to improve his condition and worsened the course of the disease
![Page 9: Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate](https://reader036.vdocument.in/reader036/viewer/2022062511/55162933550346c6758b4a78/html5/thumbnails/9.jpg)
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 CoQ10 across the blood-brain barrier in patients
Treatment of ubiquinone deficiency
![Page 10: Quinone for RC deficiency treatment. Ubiquinone function in mitochondrial respiratory chain Ubiquinone = Coenzyme Q = CoQ 10 UQ C I CII CIII CIV c Succinate](https://reader036.vdocument.in/reader036/viewer/2022062511/55162933550346c6758b4a78/html5/thumbnails/10.jpg)
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
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Cys
Ala
Fe2+
Isu1/2
NADH
from R. Lill
Nfs1
Arh1Yah1
Isa1/2
Nfu1
Yfh1
S S
S S
S S
mitochondrialFe-S protein
Mrs3/4
Grx5
Ssq1 Jac1 Mge1
extramitochondrialFe-S protein
CIA machineryCdf1, Nbp5, Nar1
cytosol
mitochondria
Iron-sulfur synthesis in yeast
Yeast Yfh1 = Human frataxin
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Iron-sulfur proteins targeted in Friedreich ataxia
UQC I
CII
CIII
CIV
c
Succinate
NADH O2
ISp
ISp
ISp : iron-sulfur protein
Innermembrane
Outermembrane
ISpAconitase
Krebscycle
ISpAconitase
Matrix
Cytosol
ISp
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Fe2+
O2ISPs
Frataxin
Respiratorychain deficiency
Tripletexpansion
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Antioxidants
Chelators
?
Fe2+
O2ISPs
Frataxin
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Idebenone
6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone
C19H29O5
MW: 338
CH2
CH2CH2
CH2CH2
CH2CH2
CH2OHCH2
CH2
C
C
C
C
C
C
O
O
CH3O
CH3O
CH3
Quinone ring Side chain
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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 ordecreased
<20%
Decreased>-20%
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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
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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)
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Quinone for RC deficiency treatment
Restoring electron flow replacement therapy in ubiquinone biosynthesis defectsubiquinone (CoQ10)
Increasing antioxidant defenses evidence of mitochondrial oxidative stress ubiquinone biosynthesis defectsidebenone