Adenine Nucleotide-Induced Contraction of the Inner Mitochondrial Membrane

Stoner, Clinton D.; Sirak, Howard D.

doi:10.1083/jcb.56.1.51

Cited by 65 publications

(28 citation statements)

References 21 publications

(26 reference statements)

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“…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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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: 99%

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

Bertagnolli¹,

Hanson²

1973

Plant Physiol.

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“…Other laboratories had provided evidence that the binding of ligands such as ADP, BKA (bongkrekic acid) and atractyloside to the ANT (adenine nucleotide translocase) might somehow influence the matrix volume [35][36][37], perhaps enabling the ANT itself to act as a pathway for K + entry [38]. This led us to propose that the Ca 2+ -induced rise in matrix PP i concentration might cause a displacement of adenine nucleotides from the ANT causing it to become leaky to K + ions.…”

Section: Mptp-dependent and -Independent Mechanisms Of Mitochondrial mentioning

confidence: 99%

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Halestrap

2010

Biochemical Society Transactions

270

239

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In addition to their normal physiological role in ATP production and metabolism, mitochondria exhibit a dark side mediated by the opening of a non-specific pore in the inner mitochondrial membrane. This mitochondrial permeability transition pore (MPTP) causes the mitochondria to breakdown rather than synthesize ATP and, if unrestrained, leads to necrotic cell death. The MPTP is opened in response to Ca(2+) overload, especially when accompanied by oxidative stress, elevated phosphate concentration and adenine nucleotide depletion. These conditions are experienced by the heart and brain subjected to reperfusion after a period of ischaemia as may occur during treatment of a myocardial infarction or stroke and during heart surgery. In the present article, I review the properties, regulation and molecular composition of the MPTP. The evidence for the roles of CyP-D (cyclophilin D), the adenine nucleotide translocase and the phosphate carrier are summarized and other potential interactions with outer mitochondrial membrane proteins are discussed. I then review the evidence that MPTP opening mediates cardiac reperfusion injury and that MPTP inhibition is cardioprotective. Inhibition may involve direct pharmacological targeting of the MPTP, such as with cyclosporin A that binds to CyP-D, or indirect inhibition of MPTP opening such as with preconditioning protocols. These invoke complex signalling pathways to reduce oxidative stress and Ca(2+) load. MPTP inhibition also protects against congestive heart failure in hypertensive animal models. Thus the MPTP is a very promising pharmacological target for clinical practice, especially once more specific drugs are developed.

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“…8) suggests that the inhibitor prevents the outward movement of the nucleotide binding site of the carrier by binding at or near the outer surface of the inner membrane either directly to the carrier or to an inner membrane component present at the same concentration as the carrier. That the inhibitor does not inhibit aggregation by causing a shift in the position of the nucleotide binding site of the carrier from an outer location to an inner location is shown by previous studies indicating that this transition occurs only upon addition of adenine nucleotides (14,26,29).…”

Section: Mechanism Of Inhibition By Carboxyatractyloside and Bongkrekmentioning

confidence: 88%

“…There is no indication of a pooling of the matrix space and, ordinarily, little or no indication of retraction of the overall intracristal + matrix space from the outer membrane. The outer membranes are usually observed to be very closely associated with the inner membranes regardless of whether or not the mitochondria are in the aggregated state, and, where clearly visible, are usually seen to be somewhat battered and broken as a result of the mitochondria having been fixed before sedimentation (28). The adenine nucleotide-and Mg2+-induced changes differ also in regard to the effect of bongkrekic acid, which, like carboxyatractyloside, is a potent inactivator of the adenine nucleotide carrier (9,16,18,32).…”

Section: T Lmentioning

confidence: 99%

“…The extents of contraction were obtained from the differences in mitochondrial OD immediately before ADP addition and 15 s after. The contraction scale is extended into the negative range to take into account a slight carboxyatractylosideinsensitive, ADP-induced decrease in mitochondrial OD which occurs simultaneously with the ADP-induced increase in mitochondrial OD shown previously (28) to be associated with inner membrane contraction. In the determinations of initial rate of phosphorylating respiration, the preincubation medium was the same as the aggregation medium except that 2.5 mM each of malate and pyruvate, 5 mM P~, and 0.1 mM ethylene glycolbis(fl-aminoethyl ether)N,N,N',N'-tetracetic acid (EGTA) were present.…”

Section: Effects Of Carboxyatractyloside and Bongkrekic Acidmentioning

confidence: 99%

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Magnesium-induced inner membrane aggregation in heart mitochondria: prevention and reversal by carboxyatractyloside and bongkrekic acid

Stoner¹,

Sirak²

1978

The Journal of Cell Biology

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Mg '~ § at an optimal concentration of 2 mM (pH 6.5) induces large increases (up to 30%) in the optical density of bovine heart mitochondria incubated under conditions of low ionic strength (< approx. 0.01). The increases are associated with aggregation (sticking together) of the inner membranes and are little affected by changes in the energy status of the mitochondria. Virtually all of a number of other polyvalent cations tested and Ag § induce increases in mitochondrial optical density similar to those induced by Mg e+, their approximate order of concentration effectiveness in respect to Mg "+ being: La 3+ > Pb "+ = Cu "+ > Cd 2+ > Zn "+ > Ag + > Mn 2+ > Ca .'+ > Mg "+. With the exception of Mg 2+, all these cations appear to induce swelling of the mitochondria concomitant with inner membrane aggregation. The inhibitors of the adenine nucleotide transport reaction carboxyatractyloside and bongkrekic acid are capable of preventing and reversing Mg"+-induced aggregation at the same low concentration required for complete inhibition of phosphorylating respiration, suggesting that they inhibit the aggregation by binding to the adenine nucleotide carrier. The findings are interpreted to indicate (a) that the inner mitochondrial membrane is normally prevented from aggregating by virtue of its net negative outer surface charge, (b) that the cations induce the membrane to aggregate by binding at its outer surface, decreasing the net negative charge, and (c) that carboxyatractyloside and bongkrekic acid inhibit the aggregation by binding to the outer surface of the membrane, increasing the net negative charge.KEY WORDS heart mitochondria inner membrane aggregation 9 polyvalent cations 9 carboxyatractyloside 9 bongkrekic acid 9 surface chargeIn the course of studies on the effects of polyvalent metal cations on adenine nucleotide-induced inner membrane contraction in heart mitochondria by the optical density (OD) method (28), we encountered considerable interference from rapid and extensive increases in mitochondrial OD induced by the cations. Increases of up to 40% were observed and appeared to be largely reversed upon induction of inner membrane contraction.

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Adenine Nucleotide-Induced Contraction of the Inner Mitochondrial Membrane

Cited by 65 publications

References 21 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

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Magnesium-induced inner membrane aggregation in heart mitochondria: prevention and reversal by carboxyatractyloside and bongkrekic acid

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