Adenine Nucleotide-Induced Contraction of the Inner Mitochondrial Membrane

Stoner, Clinton D.; Sirak, Howard D.

doi:10.1083/jcb.56.1.65

Cited by 45 publications

(10 citation statements)

References 11 publications

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“…The constancy of the matrix AdN concentrations (13) suggests this may involve an equilibrium exchange through an intermediate stage supplied by AdN transport, and this supposition is indicated in Figure 6 by the double arrow showing AdN exchange. The recent study of Stoner and Sirak (20) with bongkrekic acid discloses low affinity AdN-binding sites in addition to AdN transporting sites which may correspond to the E *AdN sites which we deduce must be present.…”

Section: Resultsmentioning

confidence: 49%

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Functioning of the Adenine Nucleotide Transporter in the Arsenate Uncoupling of Corn Mitochondria

Bertagnolli¹,

Hanson²

1973

Plant Physiol.

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Arsenate uncouples mitochondrial respiration in a process stimulated by ADP, inhibited by oligomycin, and competitively inhibited by inorganic phosphate. If mersalyl is added to corn mitochondria to block further transport of accumulated arsenate, the uncoupled respiration continues unabated due to recycling of matrix arsenate. Addition of ADP now inhibits rather than promotes respiration and the mitochondria shrink. It is established by arsenate analyses that arsenate is removed from the matrix. Oligomycin or atractyloside block the removal by inhibiting ADP-arsenate formation or transport, respectively. It is deduced that ADP-arsenate is stable in the membrane and is transported outward for hydrolysis in the external aqueous phase. Hence, ADP-arsenate formed in oxidative phosphorylation is not directly released to the matrix, and a mechanism must exist for its direct transfer to the transporter.The findings that arsenate uncoupling of mitochondrial respiration is oligomycin-sensitive (4,7,8,14,15), [6][7][8][9]15,21), and competitively inhibited by [5][6][7][8]21) has led to the opinion that instability of the ADP-As' bond formed in oxidative phosphorylation is responsible (7). It appears implicit in this view that the Fr7ATPase forms the arsenylated analog of ATP which is hydrolyzed either in the membrane or on release to the matrix, recycling As and ADP as acceptor. However, Ernster et al. (7) We report here on further studies of this phenomenon. The initial supposition is supported. The ADP-stimulation of arsenate uncoupling involves the AdN transporter, and it appears that oxidative phosphorylation-or arsenylation in this caseis accomplished without direct flux of adenine nucleotides in and out of the matrix. MATERIALS AND METHODSMitochondria. Corn mitochondria (Zea mays L. WF9(Tms)-xM14) were isolated, and recordings of oxygen consumption and percentage transmission were as previously described (10). Final suspension of the mitochondria (10-15 mg protein/ml) was in the same medium as used for the basic reaction mixture: 200 mm sucrose, 10 mm TES buffer, 1 mm MgSO, and 1 mg/ml bovine serum albumin, adjusted to pH 7.6 with KOH. Including a correction for the bovine serum albumin of the basic reaction mixture, protein concentrations were determined by the method of Lowry et al. (16). All preparations of mitochondria were checked for tight coupling by determining respiratory control and ADP/O ratios. Arsenate Transport. Radioactive 7"As (Amersham/Searle as arsenic acid in 0.04 M HCl) was mixed with potassium arsenate stock as carrier. For each experiment, a 0.1-ml aliquot of mitochondrial suspension was added to 0.9 ml of basic reaction mixture (28-29 C) with aeration by stirring. After additions (Table II), 100-1l aliquots (about 0.15 mg of protein) were withdrawn, and the mitochondria were collected on 0.45-,um pore size Millipore filters with suction being applied for 15 sec. The filters were dried, toluene based scintillation fluid (toluene-PPO-POPOP) was added, and the vials were counted.Atracty...

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Section: Resultsmentioning

confidence: 49%

“…1C) is not due to loss of As from the matrix. Very recently, Stoner and Sirak (19,20) have reported contraction of the inner membrane of heart mitochondria due to the binding of adenine nucleotides and reversal with atractyloside. This contraction produces optical changes comparable to those we report here.…”

Section: Resultsmentioning

confidence: 99%

Functioning of the Adenine Nucleotide Transporter in the Arsenate Uncoupling of Corn Mitochondria

Bertagnolli¹,

Hanson²

1973

Plant Physiol.

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“…The interconversion between these two conformations induces such a profound change in the protein structure that it causes a change in the morphology of heart mitochondria that can be detected as a change in light scattering. BKA causes light scattering to increase and the matrix to appear condensed, whilst CAT has the opposite effect [22,25,26]. The conformational changes can also be studied using endogenous tryptophan fluorescence or fluorescent ADP analogues [4].…”

Section: The Ant Exhibits Two Distinct Conformationsmentioning

confidence: 99%

The Adenine Nucleotide Translocase: A Central Component of the Mitochondrial Permeability Transition Pore and Key Player in Cell Death

Halestrap

Brenner²

2003

CMC

450

329

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In addition to its normal function, the adenine nucleotide translocase (ANT) forms the inner membrane channel of the mitochondrial permeability transition pore (MPTP). Binding of cyclophilin-D (CyP-D) to its matrix surface (probably on Pro 61 on loop 1) facilitates a calcium-triggered conformational change converting it from a specific transporter to a non-specific pore. The voltage dependent anion channel (VDAC) binds to the outer face of the ANT, at contact sites between the inner and outer membranes, and together VDAC, ANT and CyP-D probably represent the minimum MPTP configuration. The evidence for this is critically reviewed as is the structure and molecular mechanism of the carrier in its normal physiological mode. This provides helpful insights into MPTP regulation by adenine nucleotides, membrane potential and ANT ligands such as carboxyatractyloside and bongkrekic acid. Oxidative stress activates the MPTP by glutathione-mediated cross-linking of Cys 159 and Cys 256 on matrixfacing loops of the ANT that inhibits ADP binding and enhances CyP-D binding. Molecular modeling of the loop containing the ADP binding site suggests an arrangement of aspartate and glutamate residues that may provide a calcium binding site. There are other proteins that may bind to the ANT, modulating MPTP opening and hence cell death. These included members of the Bax/Bcl-2 family (both oncoproteins and tumor suppressors) and viral proteins. Vpr from HIV-1 can bind to ANT and convert it into a pro-apoptotic pore, whereas vMIA from cytomegalovirus interacts to inhibit opening. Thus the ANT may provide a molecular link between physiopathological mechanisms of infection and the regulation of MPTP function and so represents a potential therapeutic target.

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“…Recent studies indicate that proapoptotic proteins, such as Bax or Bak, interact with ANT to facilitate membrane permeabilization (16,17). Others have shown that agents that inhibit ANT activity induce mitochondrial swelling (18). It has also been postulated that mitochondrial swelling and rupture of the outer membrane may explain how cytochrome c is released (19).…”

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confidence: 99%

Distinct Effects of Saturated and Monounsaturated Fatty Acids on β-Cell Turnover and Function

et al. 2001

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Glucotoxicity and lipotoxicity contribute to the impaired ␤-cell function observed in type 2 diabetes. Here we examine the effect of saturated and unsaturated fatty acids at different glucose concentrations on ␤-cell proliferation and apoptosis. Adult rat pancreatic islets were cultured onto plates coated with extracellular matrix derived from bovine corneal endothelial cells. Exposure of islets to saturated fatty acid (0.5 mmol/l palmitic acid) in medium containing 5.5, 11.1, or 33.3 mmol/l glucose for 4 days resulted in a five-to ninefold increase of ␤-cell DNA fragmentation. In contrast, monounsaturated palmitoleic acid alone (0.5 mmol/l) or in combination with palmitic acid (0.25 or 0.5 mmol/l each) did not affect DNA fragmentation. Increasing concentrations of glucose promoted ␤-cell proliferation that was dramatically reduced by palmitic acid. Palmitoleic acid enhanced the proliferation activity in medium containing 5.5 mmol/l glucose but had no additional effect at higher glucose concentrations (11.1 and 33.3 mmol/l). The cell-permeable ceramide analog C 2 -ceramide mimicked both the palmitic acid-induced ␤-cell apoptosis and decrease in proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on ␤-cell viability. Additionally, palmitic acid but not palmitoleic acid decreased the expression of the mitochondrial adenine nucleotide translocator and induced release of cytochrome c from the mitochondria into the cytosol. Finally, palmitoleic acid improved ␤-cell-secretory function that was reduced by palmitic acid. Taken together, these results suggest that the lipotoxic effect of the saturated palmitic acid involves an increased apoptosis rate coupled with reduced proliferation capacity of ␤-cells and impaired insulin secretion. The deleterious effect of palmitate on ␤-cell turnover is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid does not affect ␤-cell apoptosis, yet it promotes ␤-cell proliferation at low glucose concentrations, counteracting the negative effects of palmitic acid as well as improving ␤-cell function. Diabetes 50:69-76, 2001

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Adenine Nucleotide-Induced Contraction of the Inner Mitochondrial Membrane

Cited by 45 publications

References 11 publications

Functioning of the Adenine Nucleotide Transporter in the Arsenate Uncoupling of Corn Mitochondria

Functioning of the Adenine Nucleotide Transporter in the Arsenate Uncoupling of Corn Mitochondria

The Adenine Nucleotide Translocase: A Central Component of the Mitochondrial Permeability Transition Pore and Key Player in Cell Death

Distinct Effects of Saturated and Monounsaturated Fatty Acids on β-Cell Turnover and Function

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