Post on 29-Jul-2015
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!