Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier.

McEnery, Maureen W.; Snowman, Adele M.; Trifiletti, Rosario Rich; Snyder, Solomon H.

doi:10.1073/pnas.89.8.3170

Cited by 641 publications

(459 citation statements)

References 53 publications

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“…The interaction between kinases, porin and ANT would provide the structural basis of contact sites between the two mitochondrial envelope membranes [32]. In the hexokinase complex, porin and ANT interacted directly as has been assumed for the benzodiazepine receptor [33]. In contrast in the creatine kinase complex, the kinase performs the interaction with the two membrane components.…”

Section: Resultsmentioning

confidence: 98%

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

et al. 1996

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In vitro incubation of isolated hexokinase isozyme I or isolated dimer of mitochondrial creatine kinase with the outer mitochondrial membrane pore led to high molecular weight complexes of enzyme oligomers. Similar complexes of hexokinase and mitochondrial creatine kinase could be extracted by 0.5% Triton X-100 from homogenates of rat brain. Hexokinase and creatine kinase complexes could be separated by subsequent chromatography on DEAE anion exchanger. The molecular weight, as determined by gel-permeation chromatography, was approximately 400 kDa for both complexes. The Mr suggested tetramers of hexokinase (monomer 100 kDa) and creatine kinase (active enzyme is a dimer of 80 kDa). The composition of the complexes was further characterised by specific antibodies. Besides either hexokinase or creatine kinase molecules the complexes contained porin and adenylate translocator. It was possible to incorporate the complexes into artificial bilayer membranes and to measure conductance in 1 M KCI. The incorporating channels had a high conductance of 6 nS that was asymmetrically voltage dependent. The complexes were also reconstituted in phospholipid vesicles that were loaded with ATP. Complex containing vesicles retained ATP while vesicles reconstituted with pure porin were leaky. The internal ATP could be used by creatine kinase and bexokinase in the complex to phosphorylate external creatine or glucose. This process was inhibited by atractyloside. The hexokinase complex containing vesicles were furthermore loaded with malate or ATP that was gradually released by addition of Ca 2+ between 100 and 600 IJNI. The liberation of malate or ATP by Ca 2+ could be inhibited by N-methylVal-4-cyclosporin, suggesting that the porin translocator complex constitutes the permeability transition pore. The results show the physiological existence of kinase porin translocator complexes at the mitochondrial surface. It is assumed that such complexes between inner and outer membrane components are the molecular basis of contact sites observed by electron microscopy. Kinase complex formation may serve three regulatory functions, firstly regulation of the kinase activity, secondly stimulation of oxidative phosphorylation and thirdly regulation of the permeability transition pore.

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Section: Resultsmentioning

confidence: 98%

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

et al. 1996

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“…These data obtained with puri®ed PT pore complexes con®rm and extend the observation that Bcl-2 prevents PT induced by atractyloside and prooxidants in isolated mitochondria . We have recently shown that this PT-inhibitory e ect of Bcl-2 is abolished by the isoquinolinecarboxamide PK11195 (Hirsch et al, 1998b), a ligand of the 18 kDa mitochondrial benzodiazepin receptor, which interacts with components of the mitochondrial megachannel (McEnery et al, 1992). Altogether, these biochemical data indicate that Bcl-2-like proteins and PT pores are functionally and molecularly interwoven.…”

Section: Molecular Composition Of the Pt Pore Complex ± Copuri®cationmentioning

confidence: 92%

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

et al. 1998

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Bcl-2 is the prototype of a class of oncogenes which regulates apoptosis. Bcl-2-related gene products with either death-promoting and death-inhibitory activity are critically involved in numerous disease states and thus constitute prime targets for therapeutic interventions. The relative amount of death agonists and antagonists from the Bcl-2 family constitutes a regulatory rheostat whose function is determined, at least in part, by selective protein-protein interactions. Bcl-2 and its homologs insert into intracellular membranes including mitochondria, the endoplasmatic reticulum and the nuclear envelope. Many of the molecular genetic, ultrastructural, crystallographic and functional studies suggest that Bcl-2-related molecules exert their apoptosis-regulatory e ects via regulating mitochondrial alterations preceding the activation of apoptogenic proteases and nucleases. Via a direct e ect on mitochondrial membranes, Bcl-2 prevents all hallmarks of the early stage of apoptosis including disruption of the inner mitochondrial transmembrane potential and the release of apoptogenic protease activators from mitochondria. The mitochondrial permeability transition (PT) pore, also called mitochondrial megachannel or multiple conductance channel, is a multiprotein complex formed at the contact site between the mitochondrial inner and outer membranes, exactly at the same localization at which Bax, Bcl-2, and Bcl-X L are particularly abundant. The PT pore participates in the regulation of matrix Ca 2+ , pH, DC m , and volume and functions as a Ca 2+ -, voltage-, pH-, and redox-gated channel with several levels of conductance and little if any ion selectivity. Experiments involving the puri®ed PT pore complex indicate that Bax, Bcl-2, and Bcl-X L exert at least part of their apoptosis-regulatory function by facilitating (Bax) or inhibiting (Bcl-2, Bcl-X L ) PT pore opening. These ®ndings clarify the principal (but not exclusive) mechanism of Bcl-2-mediated cytoprotection.

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“…One of the key elements of the PT pores is probably the adenine nucleotide translocator (ANT) (Brustovetsky and Klingenberg, 1996). The ANT has been shown to interact with outer membrane proteins including the peripheral benzodiazepin receptor (PBR, also called: endozepin receptor or receptor for the CoA-binding protein) and porin (alternative name: voltagedependent anion channel, VDAC) (McEnergy et al, 1992;Kinnally et al, 1993). In addition, soluble proteins contained in the cytosol (hexokinase), intermembrane space (creatine kinase) and in the matrix (cyclophilin D) may participate in the formation of a dynamic multiprotein ensemble that participates in the control of the PT pore (Beutner et al, 1996;Nicolli et al, 1996) (Table 1).…”

Section: Criterion Of the Switchmentioning

confidence: 99%

Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution

1997

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Recent evidence indicates that a profound alteration in mitochondrial function constitutes an obligatory early event of the apoptotic process. The molecular mechanism accounting for this alteration is mitochondrial permeability transition (PT). PT is both sufficient and necessary for apoptosis to occur. Experiments performed in cell-free systems of apoptosis demonstrate that mitochondria undergoing PT release protease activators that can trigger nuclear manifestations of apoptotis. Bcl-2 and its homologs are endogenous regulators of PT. It appears that some types of necrosis, those inhibited by Bcl-2, involve PT. If PT is a rate-limiting event of both apoptosis and necrosis, then downstream events including caspase activation and the bioenergetic consequences of PT must determine the choice between both modes of cell death. PT without caspase activation would cause necrosis. These findings have important implications for the comprehension of the apoptotic process, for the dichotomy between apoptosis and necrosis, and for the phylogeny of programmed cell death. Apoptosis may have evolved together with the endosymbiotic incorporation of aerobic bacteria (the precursors of mitochondria) into ancestral unicellular eukaryotes.

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Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier.

Abstract: The mitochondrial benzodiazepine receptor (mBzR)

Cited by 641 publications

References 53 publications

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution

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