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Quinone for RC deficiency treatment
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
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
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
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
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
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
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
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
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
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
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
Fe2+
O2ISPs
Frataxin
Respiratorychain deficiency
Tripletexpansion
Antioxidants
Chelators
?
Fe2+
O2ISPs
Frataxin
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
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%
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
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)
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