23,543 research outputs found

    Modulation of mitochondrial ion transport by inorganic polyphosphate - essential role in mitochondrial permeability transition pore

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    Inorganic polyphosphate (polyP) is a biopolymer of phosphoanhydride-linked orthophosphate residues. PolyP is involved in multiple cellular processes including mitochondrial metabolism and cell death. We used artificial membranes and isolated mitochondria to investigate the role of the polyP in mitochondrial ion transport and in activation of PTP. Here, we found that polyP can modify ion permeability of de-energised mitochondrial membranes but not artificial membranes. This permeability was selective for Ba(2+) and Ca(2+) but not for other monovalent and bivalent cations and can be blocked by inhibitors of the permeability transition pore - cyclosporine A or ADP. Lower concentrations of polyP modulate calcium dependent permeability transition pore opening. Increase in polyP concentrations and elongation chain length of the polymer causes calcium independent swelling in energized conditions. Physiologically relevant concentrations of inorganic polyP can regulate calcium dependent as well calcium independent mitochondrial permeability transition pore opening. This raises the possibility that cytoplasmic polyP can be an important contributor towards regulation of the cell death

    In vitro biochemical evaluation of methanol extract of Moringa oleifera pods on rat liver mitochondrial membrane permeability transition pore and lipid peroxidation

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    Background: Moringa oleifera is a well-known world herbal plant for its amazing medicinal and nutritional properties. The effect of methanol extract of M. oleifera can be useful in managing diseases associated with mitochondrial membrane permeability transition pore and lipid peroxidation.Methods: Evaluation was done at varying concentrations of the methanol pods extract on mitochondrial membrane permeability transition pore opening (swelling) and Fe2+- H2O2-EDTA (Fenton reaction)-induced lipid peroxidation in vitro. Five male albino rats (weighed 120-250 g) were anaesthetized and sacrificed; the liver was excised and homogenized to obtain mitochondria pellets. This study analyzed the effect of varying concentrations of methanol pods extract of M. oleifera at 50, 150, and, 300 µg/ml respectively. The effects of M. oleifera varying concentration in vitro was determined using malondialdehyde reaction quantified at 532 nm in a UV- spectrophotometer as index for lipid peroxidation and spectrophotometric absorptions at 520 nm was observed as an index of  mitochondrial membrane permeability pore respectively.Results: Varying concentrations of methanol pods extract of M. oleifera at 50, 150, and 300 µg/ml in the presence and absence of triggering agent (Ca2+) inhibited opening of mitochondria membrane permeability transition pore while 0.25, 0.50 and 1.00 mg/ml inhibited lipid peroxidation induced mitochondria of the rat liver respectively in a concentration dependent mode.Conclusion: The results suggest that methanol extract of M. oleifera pods at high concentrations (such as 300 µg/ml and 1.00 mg/ml respectively) may inhibit mitochondrial membrane permeability transition pore opening and lipid peroxidation. Keywords: Moringa oleifera, mitochondria membrane permeability transition pore, lipid peroxidatio

    Acetaminophen Induces Mitochondrial Permeability Transition in Rats Without Causing Necrotic Liver Damage

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    Mitochondrial Permeability Transition (MPT) is reported as the mechanism of acetaminophen induced hepatic damage, however, rat models are resistant to acetaminophen induced toxicity. The occurrence and degree of mitochondrial permeability transition after treatment with 400 mg kgG1 of acetaminophen in albino Wistar rats were assessed. Animals were randomly distributed into seven groups; control, 12, 24, 36, 48, 60 and 72 h based on varying time (in hour) post acetaminophen prior to sacrifice after treatment. Mitochondrial Membrane Permeability Transition (MMPT) pore opening and mitochondrial cytochrome c release were estimated. Opening of MMPT pore and cytochrome c release were observed in 12, 24, 36 and 72 h, when compared with the control group. Liver function and histological results indicated no liver damage. It is concluded that toxic dose of acetaminophen induced mitochondrial permeability transition in rat hepatic tissues without leading to necrotic damage suggesting that rat hepatic tissues evade damage by mechanisms downstream of MPT

    Regulation of mitochondrial permeability transition pore by PINK1

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    Background: Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) have been linked to familial Parkinson’s disease, but the underlying pathogenic mechanism remains unclear. We previously reported that loss of PINK1 impairs mitochondrial respiratory activity in mouse brains. Results: In this study, we investigate how loss of PINK1 impairs mitochondrial respiration using cultured primary fibroblasts and neurons. We found that intact mitochondria in PINK1−/− cells recapitulate the respiratory defect in isolated mitochondria from PINK1−/− mouse brains, suggesting that these PINK1−/− cells are a valid experimental system to study the underlying mechanisms. Enzymatic activities of the electron transport system complexes are normal in PINK1−/− cells, but mitochondrial transmembrane potential is reduced. Interestingly, the opening of the mitochondrial permeability transition pore (mPTP) is increased in PINK1−/− cells, and this genotypic difference between PINK1−/− and control cells is eliminated by agonists or inhibitors of the mPTP. Furthermore, inhibition of mPTP opening rescues the defects in transmembrane potential and respiration in PINK1−/− cells. Consistent with our earlier findings in mouse brains, mitochondrial morphology is similar between PINK1−/− and wild-type cells, indicating that the observed mitochondrial functional defects are not due to morphological changes. Following FCCP treatment, calcium increases in the cytosol are higher in PINK1−/− compared to wild-type cells, suggesting that intra-mitochondrial calcium concentration is higher in the absence of PINK1. Conclusions: Our findings show that loss of PINK1 causes selective increases in mPTP opening and mitochondrial calcium, and that the excessive mPTP opening may underlie the mitochondrial functional defects observed in PINK1−/− cells

    Loss of DJ-1 Does Not Affect Mitochondrial Respiration but Increases ROS Production and Mitochondrial Permeability Transition Pore Opening

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    Background: Loss of function mutations in the DJ-1 gene have been linked to recessively inherited forms of Parkinsonism. Mitochondrial dysfunction and increased oxidative stress are thought to be key events in the pathogenesis of Parkinson’s disease. Although it has been reported that DJ-1 serves as scavenger for reactive oxidative species (ROS) by oxidation on its cysteine residues, how loss of DJ-1 affects mitochondrial function is less clear. Methodology/Principal Findings: Using primary mouse embryonic fibroblasts (MEFs) or brains from DJ-1−/− mice, we found that loss of DJ-1 does not affect mitochondrial respiration. Specifically, endogenous respiratory activity as well as basal and maximal respiration are normal in intact DJ-1−/− MEFs, and substrate-specific state 3 and state 4 mitochondrial respiration are also unaffected in permeabilized DJ-1−/− MEFs and in isolated mitochondria from the cerebral cortex of DJ-1−/− mice at 3 months or 2 years of age. Expression levels and activities of all individual complexes composing the electron transport system are unchanged, but ATP production is reduced in DJ-1−/− MEFs. Mitochondrial transmembrane potential is decreased in the absence of DJ-1. Furthermore, mitochondrial permeability transition pore opening is increased, whereas mitochondrial calcium levels are unchanged in DJ-1−/− cells. Consistent with earlier reports, production of reactive oxygen species (ROS) is increased, though levels of antioxidative enzymes are unaltered. Interestingly, the decreased mitochondrial transmembrane potential and the increased mitochondrial permeability transition pore opening in DJ-1−/− MEFs can be restored by antioxidant treatment, whereas oxidative stress inducers have the opposite effects on mitochondrial transmembrane potential and mitochondrial permeability transition pore opening. Conclusions/Significance: Our study shows that loss of DJ-1 does not affect mitochondrial respiration or mitochondrial calcium levels but increases ROS production, leading to elevated mitochondrial permeability transition pore opening and reduced mitochondrial transmembrane potential

    An exploration of the extent and nature of reconceptualisation of pain following pain neurophysiology education: a qualitative study of experiences of people with chronic musculoskeletal pain

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    AbstractThe mitochondrial permeability transition is an inner mitochondrial membrane event involving the opening of the permeability transition pore concomitant with a sudden efflux of matrix solutes and breakdown of membrane potential. The mitochondrial FoF1 ATP synthase has been proposed as the molecular identity of the permeability transition pore. The likeliness of potential pore-forming sites in the mitochondrial FoF1 ATP synthase is discussed and a new model, the death finger model, is described. In this model, movement of a p-side density that connects the lipid-plug of the c-ring with the distal membrane bending Fo domain allows reversible opening of the c-ring and structural cross-talk with OSCP and the catalytic (αβ)3 hexamer. This article is part of a Special Issue entitled ‘EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2–6, 2016’, edited by Prof. Paolo Bernardi

    Antamanide, a Derivative of Amanita phalloides, Is a Novel Inhibitor of the Mitochondrial Permeability Transition Pore

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    Antamanide is a cyclic decapeptide derived from the fungus Amanita phalloides. Here we show that antamanide inhibits the mitochondrial permeability transition pore, a central effector of cell death induction, by targeting the pore regulator cyclophilin D. Indeed, (i) permeability transition pore inhibition by antamanide is not additive with the cyclophilin D-binding drug cyclosporin A, (ii) the inhibitory action of antamanide on the pore requires phosphate, as previously shown for cyclosporin A; (iii) antamanide is ineffective in mitochondria or cells derived from cyclophilin D null animals, and (iv) abolishes CyP-D peptidyl-prolyl cis-trans isomerase activity. Permeability transition pore inhibition by antamanide needs two critical residues in the peptide ring, Phe6 and Phe9, and is additive with ubiquinone 0, which acts on the pore in a cyclophilin D-independent fashion. Antamanide also abrogates mitochondrial depolarization and the ensuing cell death caused by two well-characterized pore inducers, clotrimazole and a hexokinase II N-terminal peptide. Our findings have implications for the comprehension of cyclophilin D activity on the permeability transition pore and for the development of novel pore-targeting drugs exploitable as cell death inhibitors

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

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    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.http://www.sciencedirect.com/science/article/B6T1J-4292HK0-5/1/3f9b42626ac2f0c2ab80880219b5d9c

    Coordinated behavior of mitochondria in both space and time: a reactive species-activated wave of mitochondrial depolarization.

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    Reactive oxygen species (ROS) can trigger a transient burst of mitochondrial ROS production via ROS activation of the mitochondrial permeability transition pore (MPTP), a phenomenon termed ROS-induced ROS release (RIRR). The goal of this study was to investigate if the generation of ROS in a discrete region of a cardiomyocyte could serve to propagate RIRR-mediated mitochondrial depolarizations throughout a cell. Our experiments revealed that localized RIRR activated either RIRR-mediated fluctuations in mitochondrial membrane potential (time period: 3–10 min) or a traveling wave of depolarization of the cell's mitochondria (velocity: ∼5 μm/min). Both phenomena appeared to be mediated by the mitochondrial permeability transition pore and eventually encompassed the majority of the mitochondrial population of both isolated rat and rabbit cardiomyocytes. Furthermore, depolarization was often reversible; the waves of depolarization were then followed by a rapid (∼40 μm/min) repolarization wave of the mitochondria. We show that the RIRR can function to communicate the mitochondrial permeability transition from one mitochondrion to another in the isolated adult cardiomyocyte

    Mitochondrial disorders in NSAIDs-induced small bowel injury

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    Recent studies using small bowel endoscopy revealed that non-steroidal anti-inflammatory drugs including low-dose aspirin, can often induce small bowel injury. Non-steroidal anti-inflammatory drugs-induced small bowel mucosal injury involves various factors such as enterobacteria, cytokines, and bile. Experimental studies demonstrate that both mitochondrial disorders and inhibition of cyclooxygenases are required for development of non-steroidal anti-inflammatory drugs-induced small bowel injury. Mitochondrion is an organelle playing a central role in energy production in organisms. Many non-steroidal anti-inflammatory drugs directly cause mitochondrial disorders, which are attributable to uncoupling of oxidative phosphorylation induced by opening of the mega channel called mitochondrial permeability transition pore on the mitochondrial membrane by non-steroidal anti-inflammatory drugs. Bile acids and tumor necrosis factor-α also can open the permeability transition pore. The permeability transition pore opening induces the release of cytochrome c from mitochondrial matrix into the cytosol, which triggers a cascade of events that will lead to cell death. Therefore these mitochondrial disorders may cause disturbance of the mucosal barrier function and elevation of the small bowel permeability, and play particularly important roles in early processes of non-steroidal anti-inflammatory drugs-induced small bowel injury. Although no valid means of preventing or treating non-steroidal anti-inflammatory drugs-induced small bowel injury has been established, advances in mitochondrial studies may bring about innovation in the prevention and treatment of this kind of injury
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