TY - JOUR
T1 - Properties of the permeability transition in VDAC1-/- mitochondria
AU - Krauskopf, Alexandra
AU - Eriksson, Ove
AU - Craigen, William J.
AU - Forte, Michael A.
AU - Bernardi, Paolo
N1 - Funding Information:
We would like to thank Dr. Valeria Petronilli for helpful discussions, and Drs. Emmanuel Pinard and Thomas Hartung (Hoffmann-La Roche Ltd., Basel) for the supply of Ro 68-3400 and the synthesis of [ 3 H]Ro 68-3400, respectively. This work was supported in part by Grants from the Italian Ministry for the University (to P.B.) and the U.S. National Institutes of Health-Public Health Service Grant GM69883 (to M.A.F. and P.B.). A.K. was supported by a Fellowship from the Swiss National Science Foundation.
PY - 2006/5
Y1 - 2006/5
N2 - Opening of the permeability transition pore (PTP), a high-conductance mitochondrial channel, causes mitochondrial dysfunction with Ca2+ deregulation, ATP depletion, release of pyridine nucleotides and of mitochondrial apoptogenic proteins. Despite major efforts, the molecular nature of the PTP remains elusive. A compound library screening led to the identification of a novel high affinity PTP inhibitor (Ro 68-3400), which labeled a ∼32 kDa protein that was identified as isoform 1 of the voltage-dependent anion channel (VDAC1) [A.M. Cesura, E. Pinard, R. Schubenel, V. Goetschy, A. Friedlein, H. Langen, P. Polcic, M.A. Forte, P. Bernardi, J.A. Kemp, The voltage-dependent anion channel is the target for a new class of inhibitors of the mitochondrial permeability transition pore. J. Biol. Chem. 278 (2003) 49812-49818]. In order to assess the role of VDAC1 in PTP formation and activity, we have studied the properties of mitochondria from VDAC1-/- mice. The basic properties of the PTP in VDAC1-/- mitochondria were indistinguishable from those of strain-matched mitochondria from wild-type CD1 mice, including inhibition by Ro 68-3400, which labeled identical proteins of 32 kDa in both wild-type and VDAC1-/- mitochondria. The labeled protein could be separated from all VDAC isoforms. While these results do not allow to exclude that VDAC is part of the PTP, they suggest that VDAC is not the target for PTP inhibition by Ro 68-3400.
AB - Opening of the permeability transition pore (PTP), a high-conductance mitochondrial channel, causes mitochondrial dysfunction with Ca2+ deregulation, ATP depletion, release of pyridine nucleotides and of mitochondrial apoptogenic proteins. Despite major efforts, the molecular nature of the PTP remains elusive. A compound library screening led to the identification of a novel high affinity PTP inhibitor (Ro 68-3400), which labeled a ∼32 kDa protein that was identified as isoform 1 of the voltage-dependent anion channel (VDAC1) [A.M. Cesura, E. Pinard, R. Schubenel, V. Goetschy, A. Friedlein, H. Langen, P. Polcic, M.A. Forte, P. Bernardi, J.A. Kemp, The voltage-dependent anion channel is the target for a new class of inhibitors of the mitochondrial permeability transition pore. J. Biol. Chem. 278 (2003) 49812-49818]. In order to assess the role of VDAC1 in PTP formation and activity, we have studied the properties of mitochondria from VDAC1-/- mice. The basic properties of the PTP in VDAC1-/- mitochondria were indistinguishable from those of strain-matched mitochondria from wild-type CD1 mice, including inhibition by Ro 68-3400, which labeled identical proteins of 32 kDa in both wild-type and VDAC1-/- mitochondria. The labeled protein could be separated from all VDAC isoforms. While these results do not allow to exclude that VDAC is part of the PTP, they suggest that VDAC is not the target for PTP inhibition by Ro 68-3400.
KW - Mitochondria
KW - Permeability transition
KW - VDAC1
UR - http://www.scopus.com/inward/record.url?scp=33745618955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745618955&partnerID=8YFLogxK
U2 - 10.1016/j.bbabio.2006.02.007
DO - 10.1016/j.bbabio.2006.02.007
M3 - Article
C2 - 16626625
AN - SCOPUS:33745618955
SN - 0005-2728
VL - 1757
SP - 590
EP - 595
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
IS - 5-6
ER -