Possible involvement of the adenine nucleotide translocase in the activation of the permeability transition pore induced by cadmium

2000 ◽  
Vol 32 (10) ◽  
pp. 1093-1101 ◽  
Author(s):  
Cecilia Zazueta ◽  
César Sánchez ◽  
Noemı́ Garcı́a ◽  
Francisco Correa
Keyword(s):  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase

The mitochondrial permeability transition pore

1999 ◽  
Vol 66 ◽  
pp. 167-179 ◽  
Author(s):  
Martin Crompton ◽  
Sukaina Virji ◽  
Veronica Doyle ◽  
Nicholas Johnson ◽  
John M. Ward
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Anion Channel ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase ◽  
Voltage Dependent Anion Channel ◽  
Inner Membrane ◽  
Membrane Pore ◽  
Voltage Dependent

This chapter reviews recent advances in the identification of the structural elements of the permeability transition pore. The discovery that cyclosporin A (CsA) inhibits the pore proved instrumental. Various approaches indicate that CsA blocks the pore by binding to cyclophilin (CyP)-D. In particular, covalent labelling of CyP-D in situ by a photoactive CsA derivative has shown that pore ligands have the same effects on the degree to which CsA both blocks the pore and binds to CyP-D. The recognition that CyP-D is a key component has enabled the other constituents to be resolved. Use of a CyP-D fusion protein as affinity matrix has revealed that CyP-D binds very strongly to 1:1 complexes of the voltage-dependent anion channel (from the outer membrane) and adenine nucleotide translocase (inner membrane). Our current model envisages that the pore arises as a complex between these three components at contact sites between the mitochondrial inner and outer membranes. This is in line with recent reconstitutions of pore activity from protein fractions containing these proteins. The strength of interaction between these proteins suggests that it may be a permanent feature rather than assembled only under pathological conditions. Calcium, the key activator of the pore, does not appear to affect pore assembly; rather, an allosteric action allowing pore flicker into an open state is indicated. CsA inhibits pore flicker and lowers the binding affinity for calcium. Whether adenine nucleotide translocase or the voltage-dependent anion channel (via inner membrane insertion) provides the inner membrane pore has not been settled, and data relevant to this issue are also documented.

scholarly journals Adenine Nucleotide Translocase-1, a Component of the Permeability Transition Pore, Can Dominantly Induce Apoptosis

1999 ◽  
Vol 147 (7) ◽  
pp. 1493-1502 ◽  
Author(s):  
Manuel K.A. Bauer ◽  
Alexis Schubert ◽  
Oliver Rocks ◽  
Stefan Grimm
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase ◽  
Cyclophilin D ◽  
Protein Aggregate ◽  
Cytochrome C Release

Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes. ANT-1 is a component of the mitochondrial permeability transition complex, a protein aggregate connecting the inner with the outer mitochondrial membrane that has recently been implicated in apoptosis. ANT-1 expression led to all features of apoptosis, such as phenotypic alterations, collapse of the mitochondrial membrane potential, cytochrome c release, caspase activation, and DNA degradation. Both point mutations that impair ANT-1 in its known activity to transport ADP and ATP as well as the NH2-terminal half of the protein could still induce apoptosis. Interestingly, ANT-2, a highly homologous protein could not lead to cell death, demonstrating the specificity of the signal for apoptosis induction. In contrast to Bax, a proapoptotic Bcl-2 gene, ANT-1 was unable to elicit a form of cell death in yeast. This and the observed repression of apoptosis by the ANT-1–interacting protein cyclophilin D suggest that the suicidal effect of ANT-1 is mediated by specific protein–protein interactions within the permeability transition pore.

scholarly journals Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore

2002 ◽  
Vol 367 (2) ◽  
pp. 541-548 ◽  
Author(s):  
Gavin P. McSTAY ◽  
Samantha J. CLARKE ◽  
Andrew P. HALESTRAP
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase ◽  
Cross Linking ◽  
Thiol Groups ◽  
Mitochondrial Permeability ◽  
Pre Treatment

Opening of the mitochondrial permeability transition pore (MPTP) is sensitized to [Ca2+] by oxidative stress (diamide) and phenylarsine oxide (PAO). We have proposed that both agents cross-link two thiol groups on the adenine nucleotide translocase (ANT) involved in ADP and cyclophilin-D (CyP-D) binding. Here, we demonstrate that blocking Cys160 with 80μM eosin 5-maleimide (EMA) or 500μM N-ethylmaleimide (NEM) greatly decreased ADP inhibition of the MPTP. The ability of diamide, but not PAO, to block ADP inhibition of the MPTP was antagonized by treatment of mitochondria with 50μM NEM to alkylate matrix glutathione. Binding of detergent-solubilized ANT to a PAO-affinity matrix was prevented by pre-treatment of mitochondria with diamide, EMA or PAO, but not NEM. EMA binding to the ANT in submitochondrial particles (SMPs) was prevented by pre-treatment of mitochondria with either PAO or diamide, implying that both agents modify Cys160. Diamide and PAO pre-treatments also inhibited binding of solubilized ANT to a glutathione S-transferase—CyP-D affinity column, both effects being blocked by 100μM EMA. Intermolecular cross-linking of adjacent ANT molecules via Cys57 by copper phenanthroline treatment of SMPs was abolished by pre-treatment of mitochondria with diamide and PAO, but not with EMA. Our data suggest that PAO and diamide cause intramolecular cross-linking between Cys160 and Cys257 directly (not antagonized by 50μM NEM) or using glutathione (antagonized by 50μM NEM) respectively. This cross-linking stabilizes the ‘c’ conformation of the ANT, reducing the reactivity of Cys57, while enhancing CyP-D binding to the ANT and antagonizing ADP binding. The two effects together greatly sensitize the MPTP to [Ca2+].

Sign in / Sign up

Export Citation Format

Share Document