scholarly journals Mobilization of Adenine Nucleotide Translocators as Molecular Bases of the Biochemical Threshold Effect Observed in Mitochondrial Diseases

2004 ◽  
Vol 279 (19) ◽  
pp. 20411-20421 ◽  
Author(s):  
Benjamin Faustin ◽  
Rodrigue Rossignol ◽  
Christophe Rocher ◽  
Giovanni Bénard ◽  
Monique Malgat ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Conformational Changes ◽  
Adenine Nucleotide ◽  
Mitochondrial Diseases ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Threshold Effect ◽  
Adenine Nucleotide Translocator ◽  
Flux Increase ◽  
Molecular Bases

The existence of a biochemical threshold effect in the metabolic expression of oxidative phosphorylation deficiencies has considerable implications for the understanding of mitochondrial bioenergetics and the study of mitochondrial diseases. However, the molecular bases of this phenomenon remain unclear. We report here a new mechanism to explain this threshold effect, based on a reserve of enzymes not initially participating in the respiratory rate that can be activated either to respond to a flux increase or to compensate for a defect induced by a mutation. We show that this mobilization occurs through 1) the assembly of inactive adenine nucleotide translocator isoform 1 subunits into oligomeric active carriers or 2) conformational changes in the adenine nucleotide translocator isoform 1 in a permeability transition pore-like structure. We discuss how these transitions are sensitive to the steady state of oxidative phosphorylation functioning or tissue and analyze their consequences on the threshold effect.

scholarly journals Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis

Oncogene ◽  
2000 ◽  
Vol 19 (2) ◽  
pp. 307-314 ◽  
Author(s):  
Paola Costantini ◽  
Anne-Sophie Belzacq ◽  
Helena LA Vieira ◽  
Nathanael Larochette ◽  
Manuel A de Pablo ◽  
...  
Keyword(s):  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocator ◽  
Permeability Transition Pore Opening ◽  
Pore Opening

Tributyltin interacts with mitochondria and induces cytochrome c release

2001 ◽  
Vol 356 (2) ◽  
pp. 621-626 ◽  
Author(s):  
Akihiko NISHIKIMI ◽  
Yukimi KIRA ◽  
Emiko KASAHARA ◽  
Eisuke F. SATO ◽  
Tomoko KANNO ◽  
...  
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Cytochrome C ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Low Doses ◽  
Adenine Nucleotide Translocator ◽  
Cytochrome C Release

Although triorganotins are potent inducers of apoptosis in various cell types, the critical targets of these compounds and the mechanisms by which they lead to cell death remain to be elucidated. There are two major pathways by which apoptotic cell death occurs: one is triggered by a cytokine mediator and the other is by a mitochondrion-dependent mechanism. To elucidate the mechanism of triorganotin-induced apoptosis, we studied the effect of tributyltin on mitochondrial function. We found that moderately low doses of tributyltin decrease mitochondrial membrane potential and induce cytochrome c release by a mechanism inhibited by cyclosporine A and bongkrekic acid. Tributyltin-induced cytochrome c release is also prevented by dithiols such as dithiothreitol and 2,3-dimercaptopropanol but not by monothiols such as GSH, N-acetyl-l-cysteine, l-cysteine and 2-mercaptoethanol. Further studies with phenylarsine oxide agarose revealed that tributyltin interacts with the adenine nucleotide translocator, a functional constituent of the mitochondrial permeability transition pore, which is selectively inhibited by dithiothreitol. These results suggest that, at low doses, tributyltin interacts selectively with critical thiol residues in the adenine nucleotide translocator and opens the permeability transition pore, thereby decreasing membrane potential and releasing cytochrome c from mitochondria, a series of events consistent with established mechanistic models of apoptosis.

Mitochondria and cell death

2000 ◽  
Vol 28 (2) ◽  
pp. 170-177 ◽  
Author(s):  
A. P. Halestrap ◽  
E. Doran ◽  
J. P. Gillespie ◽  
A. O'Toole
Keyword(s):  
Cell Death ◽  
Outer Membrane ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Ischaemia Reperfusion Injury ◽  
Mptp Opening ◽  
Cyt C

Mitochondria play a central role in both apoptosis and necrosis through the opening of the mitochondrial permeability transition pore (MPTP). This is thought to be formed through a Ca2+-triggered conformational change of the adenine nucleotide translocase (ANT) bound to matrix cyclophilin-D and we have now demonstrated this directly by reconstitution of the pure components. Opening of the MPTP causes swelling and uncoupling of mitochondria which, unrestrained, leads to necrosis. In ischaemia/reperfusion injury of the heart we have shown MPTP opening directly. Recovery of hearts correlates with subsequent closure, and agents that prevent opening or enhance closure protect from injury. Transient MPTP opening may also be involved in apoptosis by initially causing swelling and rupture of the outer membrane to release cytochrome c (cyt c), which then activates the caspase cascade and sets apoptosis in motion. Subsequent MPTP closure allows ATP levels to be maintained, ensuring that cell death remains apoptotic rather than necrotic. Apoptosis in the hippocampus that occurs after a hypoglycaemic or ischaemic insult is triggered by this means. Other apoptotic stimuli such as cytokines or removal of growth factors also involve mitochondrial cyt c release, but here there is controversy over whether the MPTP is involved. In many cases cyt c release is seen without any mitochondrial depolarization, suggesting that the MPTP does not open. Recent data of our own and others have revealed a specific outer-membrane cyt c-release pathway involving porin that does not release other intermembrane proteins such as adenylate kinase. This is opened by pro-apototic members of the Bcl-2 family such as BAX and prevented by anti-apoptotic members such as Bcl-xL. Our own data suggest that this pathway may interact directly with the ANT in the inner membrane at contact sites.

The influence of the hypoglycemic agent glycorazmulin on the functional state of mitochondria in the rats with streptozotocin-induced diabetes

2014 ◽  
Vol 60 (3) ◽  
pp. 38-42
Author(s):  
M I Asrarov ◽  
M K Pozilov ◽  
N A Ergaschev ◽  
M M Rachmatullaeva
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Permeability Transition ◽  
Experimental Diabetes ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Experimental Diabetes Mellitus ◽  
Hypoglycemic Agent ◽  
Liver And Pancreas ◽  
Swelling Rate ◽  
Streptozotocin Induced Diabetes

We have studied the state of the mitochondrial permeability transition pore (MPTP), respiration, and oxidative phosphorylation in mitochondria of the liver and pancreas of the rats with streptozotocin-induced diabetes. In addition, we considered the approaches to the correction of membraneous lesions with the help of glycorazmulin, a hypoglycemic preparation based on mumiyo (Jew's tar) and an extract from rhodiola roots and tubers (Rhodiola Semenovii A.). The mitochondria swelling rate in the liver and pancreas of the rats with experimental diabetes mellitus is known to be lower than in the unaffected animals; in other words, hepatic and pancreatic megapores in case of pathology remain open. Glycorazmulin normalizes their state and thereby eliminates the effect of spreptozotocin on mitochondria. The mitochondrial respiration rate in the liver and pancreas of the rats with experimental diabetes inceases at states V3 and V4 which results in a significant decrease of respiratory and ADP/O coefficients compared with the control values. The results of the study suggest decoupling of respiration from oxidative phosphorylation in the rats with experimental diabetes. Glycorazmulin administered per os at a dose of 50 mg/kg b.w. during 8 days eliminated functional disorders of mitochondria in the liver and pancreas of the rats, presumably by virtue of its antioxidative properties.

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