Desensitization of the Permeability Transition Pore by Cyclosporin A Prevents Activation of the Mitochondrial Apoptotic Pathway and Liver Damage by Tumor Necrosis Factor-α

Soriano, María Eugenia; Nicolosi, Luca; Bernardi, Paolo

doi:10.1074/jbc.m405297200

Cited by 68 publications

(61 citation statements)

References 66 publications

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“…As long as the energy demand can be matched, the fibers would behave normally, but dysfunction would be precipitated by increased workload and/or by increased PTP flickering, events that will eventually lead to individual muscle fiber death observed in vivo (2). This sequence of events is consistent with the occurrence of transient PTP openings in isolated mitochondria (8,9) and intact cells (10,11) and with the therapeutic effect of short-term treatment of Col6a1 Ϫ/Ϫ mice with cyclosporin A (CsA) at 10 mg⅐kg Ϫ1 ⅐day Ϫ1 (2), which desensitizes the PTP in vivo (12). Myoblasts from patients affected by Ullrich congenital muscular dystrophy (UCMD; Mendelian Inheritance in Man no.…”

supporting

confidence: 56%

Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies

Merlini

Angelin²,

Tiepolo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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193

179

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Ullrich congenital muscular dystrophy and Bethlem myopathy are skeletal muscle diseases that are due to mutations in the genes encoding collagen VI, an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle. Myoblasts from patients affected by Ullrich congenital muscular dystrophy display functional and ultrastructural mitochondrial alterations and increased apoptosis due to inappropriate opening of the permeability transition pore, a mitochondrial inner membrane channel. These alterations could be normalized by treatment with cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition. Here, we report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies. Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies. Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration. These findings demonstrate that collagen VI myopathies can be effectively treated with drugs acting on the pathogenic mechanism downstream of the genetic lesion, and they represent an important proof of principle for the potential therapy of genetic diseases. mitochondria ͉ muscular dystrophy

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supporting

confidence: 56%

Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies

Merlini

Angelin²,

Tiepolo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

193

179

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“…29 Furthermore, PTP opening may occur even in the presence of CsA at increasing Ca 2 þ loads. 30 In addition to its effects on mitochondria, our data show that p66Shc impairs Ca 2 þ homeostasis in T cells. Although in most experiments we have exploited the amplifying effects of A23187, it should be stressed that a clear effect can be detected even under basal conditions.…”

Section: Discussionmentioning

confidence: 65%

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

et al. 2006

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p66Shc, a redox enzyme that enhances reactive oxygen species (ROS) production by mitochondria, promotes T cell apoptosis. We have addressed the mechanisms regulating p66Shc-dependent apoptosis in T cells exposed to supraphysiological increases in [Ca 2 þ ] c . p66Shc expression resulted in profound mitochondrial dysfunction in response to the Ca 2 þ ionophore A23187, as revealed by dissipation of mitochondrial transmembrane potential, cytochrome c release and decreased ATP levels. p66Shc expression also caused a dramatic alteration in the cells' Ca 2 þ -handling ability, which resulted in Ca 2 þ overload after A23187 treatment. The impairment in Ca 2 þ homeostasis was ROS dependent and caused by defective Ca 2 þ extrusion due at least in part to decreased plasma membrane ATPase (PMCA) expression. Both effects of p66Shc required Ca 2 þ -dependent serine-36 phosphorylation. The mitochondrial effects of p66Shc were potentiated by but not strictly dependent on the rise in [Ca 2 þ ] c . Thus, Ca 2 þ -dependent p66Shc phosphorylation causes both mitochondrial dysfunction and impaired Ca 2 þ homeostasis, which synergize in promoting T cell apoptosis.

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“…Also, in ANT-deficient hepatocytes no altered apoptosis responses to the ligands of the Fas-and the TNF-receptor were observed. However, it is contentious [109,110] whether the PT-pore in mitochondria is activated by these cell death signals that act at the plasma membrane and hence whether an altered apoptosis (and necrosis) response could have been expected. Furthermore, since this study was published another isoform of ANT (ANT4) has been discovered in the mouse genome [111].…”

Section: Ant Knock-out Studiesmentioning

confidence: 99%

The permeability transition pore in cell death

2007

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The permeability transition pore (PT-pore) is a multi-component protein aggregate in mitochondria that comprises factors in the inner as well as in the outer mitochondrial membrane. This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel. The latter causes a collapse of the mitochondrial membrane potential and activates a chain of events that culminate in the demise of the cell. It has been controversial for some time whether the PT-pore is causative for or only amplifies a signal of cell death but novel results confirm a central role of this protein complex for cell death induction. While a considerable body of data exist on its subunit composition, recent genetic knock-out experiments suggest that the identity of the core factors of the PT-pore is still unresolved. Moreover, accumulating evidence point to a much more complex composition of this protein complex than anticipated. Here, we review the current knowledge of its subunit composition, the evidence of a role in cell death, and we propose a model for the activation of the PT-pore for cell death. The role of the PT-pore in apoptosisThe permeability transitionThe permeability transition (PT) is a sudden and sustained increase of the permeability of the inner mitochondrial membrane for solutes smaller than 1.5 kD. This has catastrophic consequences for this organelle. The mitochondrial membrane potential m , which relies on the im-permeability of the inner membrane for protons, breaks down and with it the ability of the cell to synthesize ATP. The ensuing blockade of the respiratory chain leads to the generation of reactive oxygen intermediates (ROIs), most likely via the direct transfer of electrons to molecular oxygen. Also, the high concentration of solutes in the mitochondrial matrix generates an osmotic pressure, which drives the influx of water molecules and the expansion of the extensively folded inner membrane and eventually disrupts the outer membrane leading to the release of factors that execute the suicide programme of apoptosis. Thus, the self-destruction of mitochondria via the PT is followed by the demise of the cell as a whole. This process of mitochondrial destruction was first observed in vitro but was dismissed at the time as an artefact because, among other reasons, it was inconceivable why mitochondria should dispose of a process to dismantle themselves. This changed, however, when it was shown that the PT is mediated by a protein complex, the so-called permeability transition pore (PT-pore), and that various physiological and pharmacological reagents can act on this pore and modify the deadly response of mitochondria. Finally, the realisation that cells can mount an active suicide response that is mediated in large part by mitochondria placed the PT-pore firmly on the map of researchers. In particular, the use of cyclosporine A (CsA) that can inhibit the PT-pore subunit cyc...

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Desensitization of the Permeability Transition Pore by Cyclosporin A Prevents Activation of the Mitochondrial Apoptotic Pathway and Liver Damage by Tumor Necrosis Factor-α

Abstract: We studied the effects of cyclosporin A (CsA) administration 1) on the properties of the permeability transition pore (PTP) in mitochondria isolated from the liver and 2) on the susceptibility to hepatotoxicity induced by lipopolysaccharide of Escherichia coli (

Cited by 68 publications

References 66 publications

Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies

Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

The permeability transition pore in cell death

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