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Results for “Mitochondrial Permeability Transition Pore”

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At least 19 recordsLinked to original sources

PubMed2001

Inhibitory effect of carvedilol in the high-conductance state of the mitochondrial permeability transition pore.

The mitochondrial permeability transition is a widely studied, but poorly understood, phenomenon in mitochondrial bioenergetics. It has been recognised that this phenomenon is related to the opening of a protein pore in the inner mitochondrial membrane, and that opening of this pore is the cause of some forms of mitochondrial dysfunction. In this work, we propose that carvedilol, a multi-role cardioprotective compound, may act as an inhibitor of the high-conductance state of the mitochondrial permeability transition pore, a conclusion supported by the finding that carvedilol provides differential protection against mitochondrial swelling in sucrose and KCl-based media, and that it is unable to protect against calcium-induced depolarisation of the mitochondrial membrane. We also show that carvedilol inhibits the oxidation of mitochondrial thiol groups and that, beyond causing a slight depression of the membrane potential, it has no inhibitory effect on mitochondrial calcium uptake.A decrease in the number of oxidised protein thiol groups may be the main mechanism responsible for this selective inhibition of the permeability transition pore in heart mitochondria. These effects may be important for the role of carvedilol in some cardiac pathologies.

Animals↗

PubMed2004

Role of mitochondrial permeability transition pores in mitochondrial autophagy.

During autophagy, cells rid themselves of damaged and superfluous mitochondria, as well as other organelles. This activation of mitochondrial turnover could be the result of changes in the physiological state of mitochondria. Confocal microscopy and fluorescence techniques indicate that onset of mitochondrial permeability transition is one such change. The mitochondrial permeability transition is a reversible phenomenon whereby the mitochondrial inner membrane becomes freely permeable to solutes of less than 1500 Da. At onset of the mitochondrial permeability transition, mitochondria depolarize, uncouple, and undergo large amplitude swelling due to opening of permeability transition pores, which may form by aggregation of damaged, misfolded membrane proteins. When injurious cellular stresses occur, cells may protect themselves using autophagy to remove damaged mitochondria and mutated mitochondrial DNA. Ca(2+) overloading, reactive oxygen and nitrogen species, decreased mitochondrial membrane potential, and oxidation of pyridine nucleotides and glutathione all promote mitochondrial damage and onset of the mitochondrial permeability transition. The mitochondrial permeability transition is also associated with necrosis and apoptosis after a variety of stimuli. This review emphasizes the role of the mitochondrial permeability transition as a key event in mitochondrial autophagy.

Aging↗

PubMed1997

Role of the mitochondrial permeability transition pore in apoptosis.

Mitochondrial permeability transition (PT) involves the formation of proteaceous, regulated pores, probably by apposition of inner and outer mitochondrial membrane proteins which cooperate to form the mitochondrial megachannel (= mitochondrial PT pore). PT has important metabolic consequences, namely the collapse of the mitochondrial transmembrane potential, uncoupling of the respiratory chain, hyperproduction of superoxide anions, disruption of mitochondrial biogenesis, outflow of matrix calcium and glutathione, and release of soluble intermembrane proteins. Recent evidence suggests that PT is a critical, rate limiting event of apoptosis (programmed cell death): (i) induction of PT suffices to cause apoptosis; (ii) one of the immediate consequences of PT, disruption of the mitochondrial transmembrane potential (delta psi m), is a constant feature of early apoptosis; (iii) prevention of PT impedes the delta psi m collapse as well as all other features of apoptosis at the levels of the cytoplasma, the nucleus, and the plasma membrane; (iv) PT is modulated by members of the apoptosis-regulatory bcl-2 gene family. Recent data suggest that the acquisition of the apoptotic phenotype, including characteristic changes in nuclear morphology and biochemistry (chromatin condensation and DNA fragmentation), depends on the action of apoptogenic proteins released from the mitochondrial intermembrane space.

Animals↗

PubMed2002

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

Opening of the mitochondrial permeability transition pore (MPTP) is sensitized to [Ca(2+)] 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 Cys(160) with 80 microM eosin 5-maleimide (EMA) or 500 microM 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 50 microM 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 Cys(160). 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 100 microM EMA. Intermolecular cross-linking of adjacent ANT molecules via Cys(57) 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 Cys(160) and Cys(257) directly (not antagonized by 50 microM NEM) or using glutathione (antagonized by 50 microM NEM) respectively. This cross-linking stabilizes the "c" conformation of the ANT, reducing the reactivity of Cys(57), while enhancing CyP-D binding to the ANT and antagonizing ADP binding. The two effects together greatly sensitize the MPTP to [Ca(2+)].

Adenosine Diphosphate↗

PubMed2003

The voltage-dependent anion channel is the target for a new class of inhibitors of the mitochondrial permeability transition pore.

The relevance of the mitochondrial permeability transition pore (PTP) in Ca2+ homeostasis and cell death has gained wide attention. Yet, despite detailed functional characterization, the structure of this channel remains elusive. Here we report on a new class of inhibitors of the PTP and on the identification of their molecular target. The most potent among the compounds prepared, Ro 68-3400, inhibited PTP with a potency comparable to that of cyclosporin A. Since Ro 68-3400 has a reactive moiety capable of covalent modification of proteins, [3H]Ro 68-3400 was used as an affinity label for the identification of its protein target. In intact mitochondria isolated from rodent brain and liver and in SH-SY5Y human neuroblastoma cells, [3H]Ro 68-3400 predominantly labeled a protein of approximately 32 kDa. This protein was identified as the isoform 1 of the voltage-dependent anion channel (VDAC). Both functional and affinity labeling experiments indicated that VDAC might correspond to the site for the PTP inhibitor ubiquinone0, whereas other known PTP modulators acted at distinct sites. While Ro 68-3400 represents a new useful tool for the study of the structure and function of VDAC and the PTP, the results obtained provide direct evidence that VDAC1 is a component of this mitochondrial pore.

Animals↗

PubMed2005

Salt stress-induced programmed cell death in tobacco protoplasts is mediated by reactive oxygen species and mitochondrial permeability transition pore status.

The status of mitochondrial permeability transition pore (PTP) and levels of reactive oxygen species (ROS) play key roles in regulating apoptosis in animal cells. To investigate if the PTP and cellular oxidation-reduction state are also involved in salt stress-induced programmed cell death (PCD) in tobacco (Nicotiana tabacum, cultivar BY-2) protoplasts, flow cytometry was used to simultaneously monitor ROS levels, PTP status and PCD. Increased ROS and decreased mitochondrial membrane potential (delta psi(m)) were observed before the appearance of PCD. Pre-treatment with an inhibitor of the PTP opening, cyclosporin A (CsA), effectively retarded the onset of PCD, the delta psi(m) decrease and the ROS content increase. Addition of ascorbic acid (AsA) during the salt stress significantly decreased the percentage of protoplasts undergoing PCD and ROS levels but increased delta psi(m). Hydrogen peroxide effectively induced the appearance of PCD and caused an increase in ROS and a decrease in delta psi(m). Pre-treatment of protoplasts with CsA weakened the effects of H2O2. All these results suggest that the open state of PTP and ROS are necessary elements for salt stress-induced PCD in tobacco protoplasts. The open states of PTP and ROS could promote each other suggesting that ROS could lead to a self-amplifying process. This positive feedback loop may act as an all-or-nothing switch, which is in good accordance with the hypothesis that PTP is an important coordinator and executioner of PCD in both animals and plants.

Apoptosis↗

PubMed1997

On the voltage dependence of the mitochondrial permeability transition pore. A critical appraisal.

The mitochondrial permeability transition pore, a cyclosporin A-sensitive channel, can be opened by the addition of protonophoric uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) after energy-dependent accumulation of Ca2+. We have proposed that the relevant effect of FCCP on the pore is membrane depolarization, suggesting that this channel is voltage-dependent (Bernardi, P. (1992) J. Biol. Chem. 267, 8334-8339). Here, we reconsider this hypothesis in the light of recent observations suggesting that increased production of reactive oxygen species and/or direct effects of FCCP, rather than membrane depolarization, could be the actual triggers of the FCCP-dependent permeability transition. We show that although reactive oxygen species can contribute to the permeability transition, pore opening by FCCP can still be observed under strict anaerobiosis after ATP-dependent Ca2+ accumulation and that the permeability transition can be induced by the addition of valinomycin to respiring mitochondria treated with nigericin in low potassium medium. In this system, pore opening in increasing fractions of mitochondria depends on the concentration of valinomycin, i.e. on the magnitude of the potassium current that determines the extent of membrane depolarization. We conclude that the permeability transition pore is directly modulated by the membrane potential in intact isolated rat liver mitochondria.

Animals↗

PubMed2000

Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart.

The opening of the mitochondrial permeability transition pore (PTP) has been suggested to play a key role in various forms of cell death, but direct evidence in intact tissues is still lacking. We found that in the rat heart, 92% of NAD(+) glycohydrolase activity is associated with mitochondria. This activity was not modified by the addition of Triton X-100, although it was abolished by mild treatment with the protease Nagarse, a condition that did not affect the energy-linked properties of mitochondria. The addition of Ca(2+) to isolated rat heart mitochondria resulted in a profound decrease in their NAD(+) content, which followed mitochondrial swelling. Cyclosporin A(CsA), a PTP inhibitor, completely prevented NAD(+) depletion but had no effect on the glycohydrolase activity. Thus, in isolated mitochondria PTP opening makes NAD(+) available for its enzymatic hydrolysis. Perfused rat hearts subjected to global ischemia for 30 min displayed a 30% decrease in tissue NAD(+) content, which was not modified by extending the duration of ischemia. Reperfusion resulted in a more severe reduction of both total and mitochondrial contents of NAD(+), which could be measured in the coronary effluent together with lactate dehydrogenase. The addition of 0.2 microm CsA or of its analogue MeVal-4-Cs (which does not inhibit calcineurin) maintained higher NAD(+) contents, especially in mitochondria, and significantly protected the heart from reperfusion damage, as shown by the reduction in lactate dehydrogenase release. Thus, upon reperfusion after prolonged ischemia, PTP opening in the heart can be documented as a CsA-sensitive release of NAD(+), which is then partly degraded by glycohydrolase and partly released when sarcolemmal integrity is compromised. These results demonstrate that PTP opening is a causative event in reperfusion damage of the heart.

Animals↗

PubMed1994

Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane.

The mitochondrial permeability transition pore allows solutes with a m.w. approximately less than 1500 to equilibrate across the inner membrane. A closed pore is favored by cyclosporin A acting at a high-affinity site, which may be the matrix space cylophilin isozyme. Early results obtained with cyclosporin A analogs and metabolites support this hypothesis. Inhibition by cyclosporin does not appear to require inhibition of calcineurin activity; however, it may relate to inhibition of cyclophilin peptide bond isomerase activity. The permeability transition pore is strongly regulated by both the membrane potential (delta psi) and delta pH components of the mitochondrial protonmotive force. A voltage sensor which is influenced by the disulfide/sulhydryl state of vicinal sulfhydryls is proposed to render pore opening sensitive to delta psi. Early results indicate that this sensor is also responsive to membrane surface potential and/or to surface potential gradients. Histidine residues located on the matrix side of the inner membrane render the pore responsive to delta pH. The pore is also regulated by several ions and metabolites which act at sites that are interactive. There are many analogies between the systems which regulate the permeability transition pore and the NMDA receptor channel. These suggest structural similarities and that the permeability transition pore belongs to the family of ligand gated ion channels.

Amino Acid Isomerases↗

PubMed2000

Inactivation of mitochondrial permeability transition pore by octylguanidine and octylamine.

Mitochondrial permeability transition occurs through a Ca2+-dependent opening of a transmembrane pore, whose identity has been attributed to that of the adenine nucleotide translocase (ANT). In this work, we induced permeability transition by adding 0.5 microM carboxyatractyloside. The process was evaluated analyzing Ca2+ efflux, a drop in transmembrane electric gradient, and swelling. We found that the amphiphyllic cations octylguanidine and octylamine, at the concentration of 100 microM, inhibited, almost completely, nonspecific membrane permeability. Hexylguanidine, hexylamine, as well as guanidine chloride and hydroxylamine failed to do so. The inhibition was reversed after the addition of 40 mM Li+, Na+ K+, Rb+, or Cs+; K+ was the most effective. We propose that the positive charge of the amines interact with negative charges of membrane proteins, more likely the ADP/ATP carrier, while the alkyl chain penetrates into the hydrophobic milieu of the inner membrane, fixing the reagent.

Adenosine Diphosphate↗

PubMed1998

Imaging the mitochondrial permeability transition pore in intact cells.

The involvement of mitochondrial permeability transition pore (MTP) in cellular processes is generally investigated by indirect means, such as changes in mitochondrial membrane potential or pharmacological inhibition. However, such effects could not be related univocally to MTP. In addition, source of errors could be represented by the increased retention of membrane potential probes induced by cyclosporin A (CsA) and the interactions between fluorescent probes. We developed a direct technique for monitoring MTP. Cells were co-loaded with calcein-AM and CoCl2, resulting in the quenching of the cytosolic signal without affecting the mitochondrial fluorescence. MTP inducers caused a rapid decrease in mitochondrial calcein fluorescence which, however, was not completely prevented by CsA. Besides the large and rapid efflux of calcein induced by MTP agonists, we also observed a constant and spontaneous decrease of mitochondrial calcein which was completely prevented by CsA. Thus, MTP likely fluctuates between open and closed states in intact cells.

Animals↗

PubMed2005

Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury.

The role of mitochondrial permeability transition pore (MPTP) in the mechanism of intermittent high altitude (IHA) hypoxic adaptation is not understood. Therefore, we study whether the protective effect of IHA hypoxia against ischemia-reperfusion injury is accompanied by inhibition of MPTP opening. IHA hypoxia significantly improved the functional recovery of Langendorff hearts on reperfusion and limited infarct size. In isolated myocytes, IHA hypoxia significantly improved the recovery of cell length, lowered ischemia-reperfusion-induced [Ca2+]c and [Ca2+]m overloading. Furthermore, IHA hypoxia accelerated [Ca2+]c decline during reperfusion. Opening the MPTP with atractyloside immediately at reperfusion abolished these cardioprotective effects of IHA hypoxia, but had no appreciable influence on those of normoxic hearts. IHA hypoxia prolongs the time taken to induce MPTP opening and the time taken to induce rigor contracture when myocytes subjected to oxidative stress. The data from isolated mitochondria demonstrated that IHA hypoxia prevented the decrease of ADP/O ratio, the opening of MPTP and the release of cytochrome c from mitochondria at high Ca2+ concentrations (100 and 200 microM). Inhibition of MPTP opening in the first few minutes of reperfusion accelerated [Ca2+]c decline and attenuated [Ca2+]c and [Ca2+]m overloading, which contributed to the cardioprotection of IHA hypoxic adaptation. Enhancement of the tolerance of mitochondria against Ca2+ might underlie the protective mechanism of IHA hypoxia.

Adaptation, Physiological↗

PubMed2003

Cell-type-specific opening of the retinal ganglion cell mitochondrial permeability transition pore.

PURPOSE: To study the role of the mitochondrial permeability transition pore (PTP) in apoptosis of axotomized retinal ganglion cells (RGCs) in vitro. METHODS: Primary rat retinal cultures containing DiI-labeled RGCs were treated with pharmacological agents that modulate the PTP. Ratiometric imaging of the mitochondrial membrane potential (DeltaPsi(m)) were conducted on similarly treated cultures, with the dual-emission probe JC-1, and the correlation with the results of the viability experiments were determined. RESULTS: The peripheral benzodiazepine receptor agonist PK11195 induced RGC death, but this was not inhibited by cyclosporin A (CsA), which normally maintains the PTP in the closed configuration. Paradoxically, the combination of CsA and PK11195 caused massive RGC death and decreased DeltaPsi(m), suggesting aberrant regulation of the PTP in these cells. Imaging of DeltaPsi(m) revealed morphologic changes in the mitochondria after depolarization, characterized by formation of ringlike bodies, and similar to that with the potassium ionophore valinomycin. There were no such findings with other retinal neurons or neuronally differentiated PC-12 cells. The anomalous RGC death was independent of caspase activation or reactive oxygen species production. CONCLUSIONS: These results suggest an aberrant opening of the RGC PTP and could be the result of structural differences in its components or its interaction with intracellular ligands. Unique RGC PTP behavior could underlie the pathophysiology of those mitochondrial diseases in which RGCs are specifically affected (e.g., Leber hereditary optic neuropathy).

Animals↗

PubMed1999

Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion.

The mitochondrial permeability transition pore is an inducer of cell death. During the reperfusion phase after cerebral ischemia, calcium accumulates in mitochondria, and a burst of free radical formation occurs, conditions that favor the activation of the mitochondrial permeability transition pore. Here the authors demonstrate that a blocker of the mitochondrial permeability transition pore, the nonimmunosuppressive cyclosporin A analogue N-methyl-Val-4-cyclosporin A (10 mg/kg intraperitoneally), administered during reperfusion and at 24 hours of reperfusion, diminishes infarct size in a rat model of transient focal ischemia of 2 hours' duration. The mitochondrial permeability transition pore may be an important target for drugs against stroke.

Animals↗

PubMedDate not supplied

[The role of the mitochondrial permeability transition pore in neurodegenerative processes].

AIMS: To review the role played by the mitochondrial permeability transition pore (MPTP) in different physiological and pathological processes. METHOD: Both genetic and functional alterations in mitochondria can lead to errors that trigger programmed cell death, which in turn give rise to a number of diseases that affect the nervous system. Over the last few years the mitochondrion has been seen as the link between the different signalling pathways involved in some degenerative processes. The mitochondrion seems to play an important part in the cellular decision making that leads, irreversibly, toward the execution phase in cellular death processes. This being the case, the action would be mediated by the permeability of its membranes, through the formation of the mitochondrial permeability transition pore, and would involve phenomena such as the dissipation of the mitochondrial electrochemical potential and the release of substances from within it. These substances include apoptosis inducing factor (AIF), apoptosis protease activating factor 1 (apaf 1), cytochrome c and members of the protease family: the caspases. These alterations have been described in neurodegenerative pathologies such as Alzheimer s and Parkinson s disease, amyotrophic lateral sclerosis and transmissible spongiform encephalopaties. CONCLUSIONS: Designing pharmaceutical products capable of interfering with the functions of MPTP would allow a better therapeutic approach in neurological pathologies.

Animals↗

PubMed2003

Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart.

Opening of the mitochondrial permeability transition pore (MPTP) is thought to be a critical event in mediating the damage to hearts that accompanies their reperfusion following prolonged ischaemia. Protection from reperfusion injury occurs if the prolonged ischaemic period is preceded by short ischaemic periods followed by recovery. Here we investigate whether such ischaemic preconditioning (IPC) is accompanied by inhibition of MPTP opening. MPTP opening in Langendorff-perfused rat hearts was determined by perfusion with 2-deoxy[3H]glucose ([3H]DOG) and measurement of mitochondrial [3H]DOG entrapment. We demonstrate that IPC inhibits initial MPTP opening in hearts reperfused after 30 min global ischaemia, and subsequently enhances pore closure as hearts recover. However, MPTP opening in mitochondria isolated from IPC hearts occurred more readily than control mitochondria, implying that MPTP inhibition by IPC in situ was secondary to other factors such as decreased calcium overload and oxidative stress. Hearts perfused with cyclosporin A or sanglifehrin A, powerful inhibitors of the MPTP, also recovered better from ischaemia than controls (improved haemodynamic function and less lactate dehydrogenase release). However, the mitochondrial DOG entrapment technique showed these agents to be less effective than IPC at preventing MPTP opening. Our data suggest that protection from reperfusion injury is better achieved by reducing factors that induce MPTP opening than by inhibiting the MPTP directly.

Animals↗

PubMed2002

Diazoxide opens the mitochondrial permeability transition pore and alters Ca2+ transients in rat ventricular myocytes.

BACKGROUND: The mitochondrial K(ATP) channel (mitoK(ATP)) has been implicated as an end effector or trigger of ischemic preconditioning (IP). Although a mitoK(ATP) opener, diazoxide, mimics IP, mechanisms for the cardioprotective action remain unclear. METHODS AND RESULTS: We measured Ca2+ transients (CaTs) and mitochondrial inner membrane potential (Deltapsi(m)) with confocal microscopy and the fluorescent probes fluo-4 and tetramethylrhodamine ethyl ester perchlorate in rat ventricular myocytes. Diazoxide increased the amplitudes and diastolic levels of CaTs dose dependently. The effects of diazoxide on CaTs were inhibited by the mitoK(ATP) antagonist sodium 5-hydroxydecanoic acid (100 micromol/L), whereas application of diazoxide caused little change in Deltapsi(m). After sarcoplasmic reticulum function was disabled with ryanodine and thapsigargin, the effects of diazoxide on CaTs were still observed. The opening of the mitochondrial permeability transition pore was monitored with fluorescent calcein. Diazoxide accelerated the leakage of calcein from mitochondrial matrix (16% of control; P<0.05), and this effect was inhibited by cyclosporin A (2 micromol/L). Cyclosporin A also abolished the effects of diazoxide on CaTs. Diazoxide oxidized flavoprotein fluorescence reversibly, and this effect was partially blunted by cyclosporin A (by 24%; P<0.05). CONCLUSIONS: We conclude that in rat ventricular myocytes, diazoxide modulates the opening of the mitochondrial permeability transition pore, resulting in an increase in CaTs independent of the changes in Deltapsi(m). The action of diazoxide on the mitochondrial permeability transition pore also affects the mitochondrial redox state.

Animals↗

PubMed2003

[Effect of inductors and inhibitors of the mitochondrial permeability transition pore on its opening and release of unidentified mitochondrial factor].

The release of an unidentified substance (factor) induced by sulfhydryl group (SH) modifier and mitochondrial permeability transition pore (MPT) inductor phenylarsine oxide (PAO) has been found in vitro on isolated guinea-pig and rat heart mitochondria. The factor was also released at oxidative stress. The factor release induced by PAO was inhibited by cyclosporin A (CsA), the MPT inhibitor. Protective actions of antioxidants melatonin and trolox in vitro and in vivo, as well as dithiothreitol (DTT) and diethylmaleat (DEM) were studied. The influences of nitric oxide (NO) donor, sodium nitroprusside (SNP) on the mitochondrial factor release were also studied. We have shown the participation of this agent in the regulation of factor formation after inhibition of NO-synthase activity (NOS) by aminoguanidine. The data were obtained about MPT-opening after Ca2+ loading and under the influence of the MPT inductor PAO, inhibited by CsA. The results obtained on isolated mitochondria are in a good agreement with the those on the isolated guinea-pig heart after myocardial ischemia-reperfusion. It was concluded that mitochondria are essential for the factor formation and its release under ischemia-reperfusion of the myocardium.

Animals↗