Inhibition of mitochondrial membrane bound-glutathione transferase by mitochondrial permeability transition inhibitors including cyclosporin A

Life Sciences ◽  
2010 ◽  
Vol 86 (19-20) ◽  
pp. 726-732 ◽  
Author(s):  
Enkhbaatar Ulziikhishig ◽  
Kang Kwang Lee ◽  
Quazi Sohel Hossain ◽  
Yumiko Higa ◽  
Naoki Imaizumi ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Mitochondrial Membrane ◽  
Glutathione Transferase ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Membrane Bound

Regulation of the mitochondrial permeability transition by matrix Ca2+ and voltage during anoxia/reoxygenation

2001 ◽  
Vol 280 (3) ◽  
pp. C517-C526 ◽  
Author(s):  
Paavo Korge ◽  
Henry M. Honda ◽  
James N. Weiss
Keyword(s):  
Membrane Potential ◽  
Electron Transport ◽  
Cyclosporin A ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Matrix Volume ◽  
Reoxygenation Injury ◽  
Load Size

We studied the interplay between matrix Ca2+ concentration ([Ca2+]) and mitochondrial membrane potential (Δψ) in regulation of the mitochondrial permeability transition (MPT) during anoxia and reoxygenation. Without Ca2+loading, anoxia caused near-synchronous Δψ dissipation, mitochondrial Ca2+ efflux, and matrix volume shrinkage when a critically low Po 2 was reached, which was rapidly reversible upon reoxygenation. These changes were related to electron transport inhibition, not MPT. Cyclosporin A-sensitive MPT did occur when extramitochondrial [Ca2+] was increased to promote significant Ca2+ uptake during anoxia, depending on the Ca2+ load size and ability to maintain Δψ. However, when [Ca2+] was increased after complete Δψ dissipation, MPT did not occur until reoxygenation, at which time reactivation of electron transport led to partial Δψ regeneration. In the setting of elevated extramitochondrial Ca2+, this enhanced matrix Ca2+ uptake while promoting MPT because of less than full recovery of Δψ. The interplay between Δψ and matrix [Ca2+] in accelerating or inhibiting MPT during anoxia/reoxygenation has implications for preventing reoxygenation injury associated with MPT.

scholarly journals Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions

1998 ◽  
Vol 143 (1) ◽  
pp. 217-224 ◽  
Author(s):  
Robert Eskes ◽  
Bruno Antonsson ◽  
Astrid Osen-Sand ◽  
Sylvie Montessuit ◽  
Christoph Richter ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
Mammalian Homologue

Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A–sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.

scholarly journals Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity

2016 ◽  
Vol 473 (9) ◽  
pp. 1129-1140 ◽  
Author(s):  
Andrew P. Richardson ◽  
Andrew P. Halestrap
Keyword(s):  
Cell Death ◽  
Membrane Proteins ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Molecular Identity ◽  
Permeability Transition Pores

The molecular identity of the mitochondrial permeability transition pore (MPTP), a key player in cell death, remains controversial. Here we use a novel MPTP inhibitor to demonstrate that formation of the pore involves native mitochondrial membrane proteins adopting novel conformations.

scholarly journals Mitochondrial permeability transition during hypothermic to normothermic reperfusion in rat liver demonstrated by the protective effect of cyclosporin A

1998 ◽  
Vol 336 (2) ◽  
pp. 501-506 ◽  
Author(s):  
Nathalie LEDUCQ ◽  
Marie-Christine DELMAS-BEAUVIEUX ◽  
Isabelle BOURDEL-MARCHASSON ◽  
Sylvie DUFOUR ◽  
Jean-Louis GALLIS ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Rat Liver ◽  
Mitochondrial Permeability Transition ◽  
Specific Inhibitor ◽  
Permeability Transition ◽  
Rat Liver Mitochondria ◽  
Isolated Perfused Rat Liver ◽  
Control Analysis ◽  
Top Down ◽  
Mitochondrial Permeability

The purpose of this study was to test the hypothesis that mitochondrial permeability transition might be implicated in mitochondrial and intact organ dysfunctions associated with damage induced by reperfusion after cold ischaemia. Energetic metabolism was assessed continuously by 31P-NMR on a model system of isolated perfused rat liver; mitochondria were extracted from the livers and studied by using top-down control analysis. During the temperature transition from hypothermic to normothermic perfusion (from 4 to 37 °C) the ATP content of the perfused organ fell rapidly, and top-down metabolic control analysis of damaged mitochondria revealed a specific control pattern characterized by a dysfunction of the phosphorylation subsystem leading to a decreased response to cellular ATP demand. Both dysfunctions were fully prevented by cyclosporin A, a specific inhibitor of the mitochondrial transition pore (MTP). These results strongly suggest the involvement of the opening of MTP in vivo during the transition to normothermia on rat liver mitochondrial function and organ energetics.

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