The Ca2+-induced membrane transition in mitochondria

Haworth, Robert A.; Hunter, Douglas R.

doi:10.1016/0003-9861(79)90372-2

Cited by 715 publications

(451 citation statements)

References 19 publications

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“…Elevated matrix calcium was the first factor described to activate mPTP opening (Haworth & Hunter, 1979). Although calcium overload is still considered as essential, other factors, such as oxidative stress, adenine nucleotide depletion, or high phosphate concentrations, are also involved in the formation and/or in the regulation of the pore.…”

Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

“…The mitochondrial permeability transition has been characterized by the pioneering work of Hunter and Haworth and corresponds to the sudden increase in the permeability of the inner mitochondrial membrane to molecules of molecular mass up to 1,500 Da (Haworth & Hunter, 1979; Hunter & Haworth, 1979a, 1979b). The opening is due to a nonspecific pore called the mitochondrial permeability transition pore (mPTP) occurring when mitochondria become overloaded with calcium.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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“…Consequently, the inner mitochondrial membrane becomes more permeable to ions, resulting in loss of Dc m . This is the MPT (Haworth and Hunter, 1979). The resulting oncotic influx of water structurally deforms and functionally impairs processes, such as ATP production, that occur within mitochondrial matrix.…”

Section: Bnip3 and Nix/bnip3l In Nonapoptotic Programmed Cell Deathmentioning

confidence: 99%

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

Dorn

Kirshenbaum

2008

Oncogene

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Programmed cardiac myocyte death contributes to pathological ventricular remodeling and the progression of myocardial infarction or pressure overload hypertrophy to dilated cardiomyopathy. Recent work has identified importance of stress-mediated transcriptional induction of BNIP3 (BCL2 and 19-kDa interacting protein-3) and NIX/BNIP3L in cardiac remodeling. Here, the regulatory mechanisms for these two factors in the heart and their effects on programmed cardiomyocyte death are reviewed, with a focus on information derived from studies using mouse models of cardiac BNIP3 and NIX/BNIP3L overexpression and gene ablation.

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“…This multimeric structure mediates Ca 2+ and oxidative stress-inducible collapse of the inner mitochondrial membrane potential (∆Ψ m ) by forming a large non-specific megachannel with a size cutoff of around 1500 Daltons (Haworth and Hunter, 1979;Petronilli et al, 1994). Tremendous growth in interest in the physiology of the PTPC has arisen recently through its involvement in the regulation of both apoptotic and necrotic cell death, processes which involve early ∆Ψ m dissipation (Lemasters et al, 1998).…”

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confidence: 99%

Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species

et al. 2001

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SummaryResistance to apoptosis is a major obstacle preventing effective therapy for malignancy. Mitochondria localized anti-death proteins of the Bcl-2 family play a central role in inhibiting apoptosis and therefore present valid targets for novel therapy. The peripheral benzodiazepine receptor (PBR) shares a close physical association with the permeability transition pore complex (PTPC), a pivotal regulator of cell death located at mitochondrial contact sites. In this study we investigated the cytotoxicity of the PBR ligand, PK11195, in the micromolar concentration range. PK11195 induced antioxidant inhibitable collapse of the inner mitochondrial membrane potential (∆Ψ m ) and mitochondrial swelling in HL60 human leukaemia cells, but not in SUDHL4 lymphoma cells (which exhibited a higher level of reduced glutathione and relative tolerance to chemotherapy or pro-oxidant induced ∆Ψ m dissipation). PK11195 induced the production of hydrogen peroxide that was not inhibited by Bcl-2 transfection, nor depletion of mitochondrial DNA. ROS production was however blocked by protonophore, implicating a requirement for ∆Ψ m . Our findings suggest that PK11195-induced cytotoxicity relies upon Bcl-2 resistant generation of oxidative stress; a process only observed at concentrations several orders of magnitude higher that required to saturate its receptor. 1397-1404 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.1788, available online at http://www.idealibrary.com on http://www.bjcancer.com methyl-N-methyl-N-(1-methylpropyl)-isoquinoline carboxamide (PK11195), carbonylcyanide m-chlorophenylhdrazone (CCCP), propidium iodide and all cell culture reagents were purchased from Sigma-Aldrich Ltd, UK. FITC-conjugated mouse antihuman Bcl-2 monoclonal antibody, and the Dako intrastain fixation/permeabilization kit were purchased from Dako, UK. Cell culture and treatmentsHL60, KG1A, K652 cells stably transfected with the Bcl-2 gene (K562 B4) or vector only (K562 N2) (kindly provided by Dr DE Banker and Dr F Applebaum, The Fred Hutchinson Cancer Research Center, USA), and SUDHL4 lymphoma cell lines, were maintained in exponential suspension cultures in RPMI 1640 medium supplemented with 10% fetal calf serum, 5 mM glutamine, 100 µg ml -1 streptomycin and 100 U ml -1 penicillin. Cells were grown in a humidified atmosphere of 5% CO 2 /95% air at 37˚C. PK11195 was dissolved in ethanol at a stock concentration of 8.7 mg ml -1 , and added to cells at a 75 µM final concentration for 4 hours; vehicle alone was also used in medium. To test the effect of an antioxidant on PK11195 activity, cells were treated with 10 mM N-acetylcysteine for 45 minutes prior to treatment with PK11195.Cells were incubated with VP16, or ara-C at 10 µM final concentration for 24 hours, or with the thiol crosslinking prooxidant, diamide, at 100 µM concentration for 24 hours. The protonophore CCCP was used to dissipate ∆Ψ m by treating cells at a concentration of 10 µM for 15 minutes prior to treatment with PK11195. Depletion of mitochondrial DNAKG1A cells ...

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The Ca2+-induced membrane transition in mitochondria

Cited by 715 publications

References 19 publications

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondria and aging: A role for the mitochondrial transition pore?

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species

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