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