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John J Lemasters - One of the best experts on this subject based on the ideXlab platform.

  • role of Mitochondrial Permeability transition pores in Mitochondrial autophagy
    The International Journal of Biochemistry & Cell Biology, 2004
    Co-Authors: Sara Rodriguezenriquez, Lihua He, John J Lemasters
    Abstract:

    Abstract 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.

  • inhibition of the Mitochondrial Permeability transition by the nonimmunosuppressive cyclosporin derivative nim811
    Molecular Pharmacology, 2002
    Co-Authors: P C Waldmeier, T Qian, J J Feldtrauer, John J Lemasters
    Abstract:

    Cyclosporin A (CsA) shows cytoprotective properties in many cellular and in vivo models that may depend on interference of the interaction of cyclophilin A with calcineurin or of cyclophilin D with the Mitochondrial Permeability transition (PT) pore. The nonimmunosuppressive cyclosporin derivative N -methyl-4-valine-cyclosporin (PKF220-384) inhibits the Mitochondrial Permeability transition (MPT) like CsA but without calcineurin inactivation. PKF220-384 has been used to discriminate between PT pore- and calcineurin mediated effects but is no longer available. Here, we evaluated the effects of another nonimmunosuppressive cyclosporin derivative, N -methyl-4-isoleucine-cyclosporin (NIM811) on the MPT. Using two newly developed microtiter plate assays, one measuring Mitochondrial swelling from absorbance and the other measuring Mitochondrial membrane potential from changes in safranin fluorescence, we show that NIM811 blocks the MPT induced by calcium and inorganic phosphate, alone or in combination with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the complex I inhibitor rotenone, and the prooxidant t -butylhydroperoxide. NIM811 was equipotent to CsA and half as potent as PKF220-384. Additionally, we show that NIM811 blocks cell killing and prevents in situ Mitochondrial inner membrane permeabilization and depolarization during tumor necrosis factor-α–induced apoptosis to cultured rat hepatocytes. NIM811 inhibition of apoptosis was equipotent with CsA except at higher concentrations: CsA lost efficacy but NIM 811 did not. We conclude that NIM811 is a useful alternative to PKF220-384 to investigate the role of the Mitochondrial Permeability transition in apoptotic and necrotic cell death.

  • The Mitochondrial Permeability transition in toxic, hypoxic and reperfusion injury
    Molecular and Cellular Biochemistry, 1997
    Co-Authors: John J Lemasters, A L Nieminen, T Qian, L C Trost, B Herman
    Abstract:

    Opening of a non-specific, high conductance Permeability transition pore or megachannel in the inner Mitochondrial membrane causes onset of the Mitochondrial Permeability transition, which is characterized by Mitochondrial swelling, depolarization and uncoupling. Inducers of the Permeability transition include Ca2+, oxidant stress and a permissive pH greater than 7.0. Blockers include cyclosporin A, trifluoperazine and pH < 7. Using laser scanning confocal microscopy, we developed techniques to visualize onset of the Mitochondrial Permeability transition in situ in living cells. In untreated cells, the Permeability transition pore is continuously closed and does not ‘flicker’ open. By contrast, the pore opens in liver and heart cells after exposure to oxidant chemicals, calcium ionophore, hypoxia and ischemia/reperfusion, causing Mitochondrial uncoupling and aggravation of ATP depletion. In injury to hepatocytes from tert-butylhydroperoxide, an analog of lipid hydroperoxides generated during oxidative stress, onset of the Mitochondrial Permeability transition is preceded by oxidation of Mitochondrial pyridine nucleotides, Mitochondrial generation of oxygen radicals and an increase of Mitochondrial Ca2+, all inducers of the Mitochondrial Permeability transition. In ischemia, the acidosis of anaerobic metabolism protects strongly against cell death. During reperfusion, recovery of pH to normal levels is a stress that actually precipitates cell killing. Onset of the Mitochondrial Permeability transition may be responsible, in part, for this pH-dependent injury, or pH paradox. The Mitochondrial Permeability transition may also be responsible for a variety of pathological phenomena. In particular, the Mitochondrial Permeability transition may underlie Reye’s syndrome and Reye’s-like drug toxicities. In conclusion, multiple mechanisms contribute to cell injury after hypoxia, ischemia/reperfusion and toxic chemicals, but a common final pathway leading to acute cellular necrosis may be ATP depletion after Mitochondrial failure. One important mechanism causing Mitochondrial failure is the Mitochondrial Permeability transition, which both uncouples oxidative phosphorylation and accelerates ATP hydrolysis. Interventions that block this pH-dependent phenomenon protect against onset of cell death. (Mol Cell Biochem 174: 159–165, 1997)

  • Mitochondrial Permeability transition in hepatocytes induced by t buooh nad p h and reactive oxygen species
    American Journal of Physiology-cell Physiology, 1997
    Co-Authors: A L Nieminen, B Herman, Aaeon M Byrne, John J Lemasters
    Abstract:

    Tert-butyl hydroperoxide (t-BuOOH) induces the Mitochondrial Permeability transition (MPT) in hepatocytes, leading to cell death. Using confocal microscopy, we visualized pyridine nucleotide oxidat...

Michel Ovize - One of the best experts on this subject based on the ideXlab platform.

Paolo Pinton - One of the best experts on this subject based on the ideXlab platform.

  • A New Current for the Mitochondrial Permeability Transition
    Trends in Biochemical Sciences, 2019
    Co-Authors: Massimo Bonora, Paolo Pinton
    Abstract:

    Mitochondrial F1/FO ATP synthase participation in the Mitochondrial Permeability transition pore complex (PTPC) remains controversial. Neginskaya et al. (Cell Rep. 2019;26:11–17) reported an unexpected current with PTPC-like properties in F1/FO ATP synthase C subunit knockout cells that could explain part of the conflictual literature.

  • The Mitochondrial Permeability Transition Pore
    Mitochondrial Biology and Experimental Therapeutics, 2018
    Co-Authors: Claudia Morganti, Massimo Bonora, Giampaolo Morciano, Carlotta Giorgi, Mariusz R. Wieckowski, Luigi Sbano, Giorgio Aquila, Gianluca Campo, Paolo Pinton
    Abstract:

    The Mitochondrial Permeability transition (MPT) consists of an abrupt increase in the Permeability of the inner Mitochondrial membrane to low molecular weight solutes, resulting in the osmotic breakout of the organelle. MPT drives cell death and provides an etiological contribution to several human disorders characterized by the acute loss of post-mitotic cells. These conditions include ischemia/reperfusion injury, cancer and neurodegenerative disorders. However, precise knowledge of the structure and regulators of the supramolecular entity that induces MPT, the so-called Permeability transition pore complex (PTPC), is lacking and this constitutes a substantial obstacle in the development of MPT-targeting agents with clinical applications. Here we report the current evidences about molecular structure and regulatory components of PTPC. In particular we pay attention on new two proteins which recently were added to the list of PTPC components: the Mitochondrial F1FO ATP synthase, particularly and the SPG7 paraplegin matrix AAA peptidase subunit. At least a detailed overview of MPT contribution to pathological condition is provided, focusing on the idea that to develop therapeutic drugs, it will be fundamental to understand the molecular composition of the PTPC.

  • Other bricks for the correct construction of the Mitochondrial Permeability transition pore complex.
    Cell Death and Disease, 2017
    Co-Authors: Giampaolo Morciano, Massimo Bonora, Carlotta Giorgi, Paolo Pinton
    Abstract:

    Other bricks for the correct construction of the Mitochondrial Permeability transition pore complex

  • molecular identity of the Mitochondrial Permeability transition pore and its role in ischemia reperfusion injury
    Journal of Molecular and Cellular Cardiology, 2015
    Co-Authors: Giampaolo Morciano, Massimo Bonora, Carlotta Giorgi, Mariusz R. Wieckowski, Gianluca Campo, Silvia Punzetti, Rita Pavasini, Paolo Pinton
    Abstract:

    article i nfo The Mitochondrial Permeability transition is a key event in cell death. Intense research efforts have been focused on elucidating the molecular components of the Mitochondrial Permeability transition pore (mPTP) to improve the understanding and treatment of various pathologies, including neurodegenerative disorders, cancer and car- diac diseases. Several molecular factors have been proposed as core components of the mPTP; however, further investigation has indicated that these factors are among a wide range of regulators. Thus, the scientific commu- nity lacksa clearmodelof themPTP. Here,wereviewthe molecular factors involved intheregulation andforma- tion of the mPTP. Furthermore, we propose that the Mitochondrial ATP synthase, specifically its c subunit, is the central core component of the mPTP complex. Moreover, we discuss the involvement of the mPTP in ischemia and reperfusion as well as the results of clinical studies targeting the mPTP to ameliorate ischemia-reperfusion injury. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".

  • The Mitochondrial Permeability transition pore and cancer: molecular mechanisms involved in cell death
    Frontiers in Oncology, 2014
    Co-Authors: Massimo Bonora, Paolo Pinton
    Abstract:

    Since its discovery in the 1970s, the Mitochondrial Permeability transition (MPT) has been proposed to be a strategic regulator of cell death. Intense research efforts have focused on elucidating the molecular components of the MPT because this knowledge may help to better understand and treat various pathologies ranging from neurodegenerative and cardiac diseases to cancer. In the case of cancer, several studies have revealed alterations in the activity of the Mitochondrial Permeability transition pore (mPTP) and have determined its regulatory mechanism; these studies have also suggested that suppression of the activity of the mPTP, rather than its inactivation, commonly occurs in solid neoplasms. This review focuses on the most recent advances in understanding mPTP regulation in cancer and highlights the ability of the mPTP to impede the mechanisms of cell death.

Hyun Hee Ko - One of the best experts on this subject based on the ideXlab platform.

  • Differential Involvement of Mitochondrial Permeability Transition in Cytotoxicity of 1-Methyl-4-Phenylpyridinium and 6-Hydroxydopamine
    Molecular and Cellular Biochemistry, 2006
    Co-Authors: Woo Jae Park, Hyun Hee Ko
    Abstract:

    Defects in Mitochondrial function have been shown to participate in the induction of neuronal cell injury. The aim of the present study was to assess the influence of the Mitochondrial membrane Permeability transition inhibition against the toxicity of 1-methyl-4-phenylpyridinium (MPP^+) and 6-hydroxydopamine (6-OHDA) in relation to the mitochondria-mediated cell death process and role of oxidative stress. Both MPP^+ and 6-OHDA induced the nuclear damage, the changes in the Mitochondrial membrane Permeability, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species and the depletion of GSH in differentiated PC12 cells. Cyclosporin A (CsA), trifluoperazine and aristolochic acid, inhibitors of Mitochondrial Permeability transition, significantly attenuated the MPP^+-induced Mitochondrial damage leading to caspase-3 activation, increased oxidative stress and cell death. In contrast to MPP^+, the cytotoxicity of 6-OHDA was not reduced by the addition of the Mitochondrial Permeability transition inhibitors. The results show that the cytotoxicity of MPP^+ may be mediated by the Mitochondrial Permeability transition formation, which is associated with formation of reactive oxygen species and the depletion of GSH. In contrast, the 6-OHDA-induced cell injury appears to be mediated by increased oxidative stress without intervention of the Mitochondrial membrane Permeability transition.

Derek M Yellon - One of the best experts on this subject based on the ideXlab platform.