Man et al., 2002

Leber’s hereditary optic neuropathy

ND1, ND4,ND5, ND6

ATP synthesis? Free radicals? Redox imbalance? Apoptosis?

Man et al., 2002

Leber’s hereditary optic neuropathy

The mitochondrial respiratory chain

Q

Haefeli et al, 2011

NAD(P)H:quinone oxidoreductases (NQOs) catalyze the reduction of quinones

Q

Short-chainquinones

Idebenone

CH2OH

H3CO CH3

H3CO

O

O

Used in LHON, MELAS and Leigh syndrome but also in Friedreich’s ataxia, Huntington disease, Alzheimer disease

Mouse hepatocytes

In vitro Ex vivo

0 20 40

20

40

60

80

100

120

TM

RM

fluo

resc

ence

, % o

f ini

tial v

alue

0 20 40

Time, min

FOR F

O R

Porcelli et al (2009)

TMRM

fluo

resc

ence

(% o

f ini

tial v

alue

) Oligo

RotAA

Time, min0 20 40 60

50

100

150 DTT +IdB

HQB17 cybrids

+CsA

FCCPIdB

Time, min0 20 40

50

100

150

O

O

CH3

MeO

MeO

CH OH2

OH

OH

CH3

MeO

MeO

CH OH2

Two effects of idebenone

reduced

oxidizedO

O

CH3

MeO

MeO

CH OH2

OH

OH

CH3

MeO

MeO

CH OH2

PTP opening

Two effects of idebenone

Idebenone is rapidlymetabolized in vivo

QS10QS6 QS4Idebenone

Kutz et al, 2009

Bodmer et al, 2009

Idebenone metabolites

Synthesized by the laboratory of Maurizio Prato (Trieste)

IdB

10 min

5 µM Ca2+

O

O

MeO

MeOCOOH

QS10

QS8

QS6

QS4

O

O

MeO

MeOCOOH

O

O

MeO

MeOCOOH

O

O

MeO

MeOCOOH

QS10

QS48

Idebenone metabolites do not sensitize the PTP to Ca2+

Effects of idebenone and its metabolites on the permeability transition pore

Time, min

TMRM

fluo

resc

ence

, % o

f ini

tial v

alue

40

80

120

160 DTTRot

Oligo

AAFCCP

40 80

RotOligo

AA

FCCP

QSxR

40 800 0

0

Effect of reduced QSx on respiration of XTC.UC1 cells (Complex I defect)

FCCP AAO R

20 40 60 80

300

500

100OCR

, pm

oles

/min

Time, min

+QSxR

Idebenone QSx

QSx-pretreatment protects from rotenone toxicity

In vivo effects of idebenone and QSx: Zebrafish as a model for complex I deficiencies

Rotenone Rotenone Rotenone

Zebrafish coiling events

1

2

3

4

5

IdB QS10 Rot

spon

tane

ous

coili

ng e

vent

s (e

very

15

sec)

***

Marco Schiavone

p 0,005

IdB+Rot

QS10+Rot

**

p 0.01

20

60

100

20 40 60

RotuntreatedRot (0.1 µM)

% s

urvi

val

Hours post fertilization

IDB

IDBIDB + Rot

IDB /QSx

QSxQSx + Rot

Zebrafish survival to rotenone toxicity

University of Padova

Valentina GiorgioValeria PetronilliMarco SchiavoneFrancesco Argenton

University of Bologna

Valerio CarelliAnna Maria GhelliGiorgio LenazMichela Rugolo

Telethon Program Project Therapeutic strategies to combat mitochondrial disorders

University of Padova Models of mitochondrial Fondazione Cariparo diseases

University of Trieste

Marco CariniTatiana Da RosMaurizio Prato

Department of Biomedical Sciences

University of Padova, Italy

Thank you!