Cyclophilin D, a Component of the Permeability Transition-Pore, Is an Apoptosis Repressor

Schubert, Alexis; Grimm, Stefan

doi:10.1158/0008-5472.can-03-0476

Cited by 107 publications

(91 citation statements)

References 71 publications

(72 reference statements)

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“…However, a substantial body of evidence indicates that cypD has anti-apoptotic activities. Importantly, we [120,121] and others [122] have recently found that enforced cypD expression can specifically repress the activation of the PT-pore. Another study in neuronal cells also observed apoptosis inhibition (but sensitisation for necrosis) by cypD overexpression [123].…”

Section: Overexpression Studies On Cypdmentioning

confidence: 57%

“…Moreover, there is accumulating evidence that cyclosporin A can induce apoptosis in certain cells [124][125][126][127]. In fact, the clinical use of CsA is still limited by its potential toxicity [128,129] and a specific inhibition of the PT-pore as observed with cypD [120,122] would be therapeutically of high interest. Hence, it is important to determine how overexpressed cypD induces or inhibits cell death.…”

Section: Overexpression Studies On Cypdmentioning

confidence: 99%

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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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Section: Overexpression Studies On Cypdmentioning

confidence: 57%

Section: Overexpression Studies On Cypdmentioning

confidence: 99%

The permeability transition pore in cell death

2007

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“…However, mouse knockout studies led to the conclusion that ANT would not (always) be required for apoptotic MOMP (Kokoszka et al, 2004). Recent evidence suggests that some ANT isoforms (ANT1, ANT3) are apoptogenic while others are not (ANT2) (Schubert and Grimm, 2004;Zamora et al, 2004). In 2005, a fourth ANT isoform (ANT4) has been identified in man (Dolce et al, 2005) and mouse (Rodic et al, 2005) by means of two independent experimental approaches.…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…14 By contrast, it has also been reported that in some instances cyclophilin D prevents apoptotic cell death through modulation of Bcl-2 and by promoting the binding of HKII to the mitochondria. 15,16 Shulga et al 12 demonstrated that a decrease of SIRT3 activity enhances the binding of HKII to the mitochondria by increasing cyclophilin D activity, potentially making the cells resistant to apoptosis.Apoptotic cell death is characterized by well-defined biochemical and morphological changes such as plasma membrane blebbing, DNA fragmentation and changes in the MPT with release of mitochondrial proteins. 17 Mitochondria have a central role in regulating the apoptotic process because many apoptogenic proteins such as cytochrome c,…”

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confidence: 99%

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SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

et al. 2012

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Mitochondrial sirtuin 3 (SIRT3) mediates cellular resistance toward various forms of stress. Here, we show that in mammalian cells subjected to hypoxia and staurosporine treatment SIRT3 prevents loss of mitochondrial membrane potential (DW mt ), intracellular acidification and reactive oxygen species accumulation. Our results indicate that: (i) SIRT3 inhibits mitochondrial permeability transition and loss of membrane potential by preventing HKII binding to the mitochondria, (ii) SIRT3 increases catalytic activity of the mitochondrial carbonic anhydrase VB, thereby preventing intracellular acidification, Bax activation and apoptotic cell death. In conclusion we propose that, in mammalian cells, SIRT3 has a central role in connecting changes in DW mt , intracellular pH and mitochondrial-regulated apoptotic pathways. Cell Death and Differentiation (2012) 19, 1815-1825 doi:10.1038/cdd.2012 published online 18 May 2012 Sirtuins are a family of protein highly conserved in both prokaryotes and eukaryotes. 1 The name derives from the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), the first known sirtuin, that, by silencing chromatin via deacetylation of histones, regulates both replicative and overall life span. 2 In mammals, seven Sir2 homologs, designated SIRT1 through SIRT7 have been identified, that regulate a wide range of intracellular processes including metabolism, longevity, aging, cancer and response to stress. 3-5 These proteins are characterized by an evolutionarily conserved sirtuin core domain 6 that contains the catalytic and nicotinamide adenine dinucleotide (NAD þ )-binding domain. Each sirtuin catalyzes protein deacetylation or adenosine diphosphate (ADP) ribosylation in vitro, requires NAD þ for enzymatic activity and generates nicotinamide, which then acts as a negative feedback inhibitor. 7 Because of the NAD þ requirement, sirtuins are categorized as class III histone deacetylases. 8 Mammalian sirtuins show distinct acetylated protein substrates and are localized in distinct subcellular compartments. Sirtuin 1 (SIRT1), SIRT6 and SIRT7 are in the nucleus, SIRT2 is primarily cytosolic and SIRT3, SIRT4 and SIRT5 are in the mitochondria. 9 Mitochondrial sirtuins participate in the regulation of ATP production, metabolism, apoptosis and cell signaling. 10 Among the three mitochondrial sirtuins, SIRT3 controls the global lysine acetylation of these organelles. 11 SIRT3 mediates cellular resistance toward various forms of stress by maintaining genomic stability and mitochondrial integrity. For example, SIRT3 influences cell survival by regulating the state of the mitochondrial permeability transition (MPT). However, the precise effects of SIRT3 on MPT are still not clear. In fact, some reports have shown that SIRT3 would deacetylate and inhibit the enzymatic activity of cyclophilin D 12 with the following dissociation from adenine nucleotide translocator, which, in turn, promotes detachment of hexokinase II (HKII) from voltage-dependent anion channel. Inhibition of cyclophilin D i...

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Cyclophilin D, a Component of the Permeability Transition-Pore, Is an Apoptosis Repressor

Cited by 107 publications

References 71 publications

The permeability transition pore in cell death

The permeability transition pore in cell death

Mitochondria as therapeutic targets for cancer chemotherapy

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

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