The mitochondrial permeability transition from <i>in vitro</i> artifact to disease target

Bernardi, Paolo; Krauskopf, Alexandra; Basso, Emy; Petronilli, Valeria; Blalchy‐Dyson, Elizabeth; Lisa, Fabio Di; Forte, Michael

doi:10.1111/j.1742-4658.2006.05213.x

Cited by 600 publications

(514 citation statements)

References 272 publications

(326 reference statements)

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“…Bcl-2-family proteins also may modulate activity of the mitochondrial permeability transition pore, 54 a poorly understood regulator of inner membrane permeability. 55 The significance of whether MDPs exclusively affect MOP versus the possibility that they also control some aspects of inner membrane permeability resides at least in part in the need for inner membrane integrity to maintain the H þ gradient that creates the driving force for ATP generation and proper flow of electrons through the respiratory chain. Disruption of inner membrane function thus leads of generation of reactive oxygen species and ATP depletion, typically culminating in necrosis.…”

Section: Cellular Actions Of Mdpsmentioning

confidence: 99%

“…Accumulation of Ca 2 þ in mitochondria, when excessive, can lead to depolarization and loss of osmotic homeostasis, followed by organellar swelling and subsequent membrane rupture to release apoptogenic proteins, disturb electron transport, ablate ATP production, and cause cell death. 55 However, the reductions in resting ER Ca 2 þ seen in Bax/Bak doubly-deficient cells (or cells overexpressing Bcl-2 or Bcl-X L ) may have myriad other affects on Ca 2 þ -dependent signaling events in cells, and many of those may not be particularly germane to cell death regulation.…”

Section: Cellular Actions Of Mdpsmentioning

confidence: 99%

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Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

2006

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Bcl-2-family proteins are central regulators of cell life and death. At least three major classes of Bcl-2-family proteins have been delineated, including proapoptotic proteins that contain several conserved regions of sequence similarity (termed 'multidomain'). In mammals, the multidomain proteins (MDPs) of the Bcl-2 family include Bax, Bak, and Bok. The founding member of the MDP group of Bcl-2-family proteins was discovered by Stanley Korsmeyer and co-workers, initiating an exciting area of cell death research. The status of current knowledge about the mechanisms and functions of MDPs is reviewed here, and some areas for future research are outlined. Therapeutic opportunities emerging from a growing understanding of MDPs with respect to their threedimensional structures, biochemical actions, and roles in disease raise hopes that the foundation of basic research laid by Korsmeyer and others will eventually be translated into clinical benefits, leaving a legacy that benefits the world for many decades.

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Section: Cellular Actions Of Mdpsmentioning

confidence: 99%

Section: Cellular Actions Of Mdpsmentioning

confidence: 99%

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

2006

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“…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 cyclophilin D and also reduces cell death in many scenarios played a crucial role to establish the importance of the PT-pore [1].…”

Section: The Role Of the Pt-pore In Apoptosismentioning

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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“…Thus, of the proposed components of the PTP, convincing genetic and biochemical evidence only exists for the role of CyP-D in the regulation of PTP activity. Given these considerations then, we must admit that the proteins actually forming core components of the PTP remain a mystery (see Bernardi et al 16 for a detailed discussion).…”

Section: Inner Membrane Permeability Transitionmentioning

confidence: 99%

The permeability transition and BCL-2 family proteins in apoptosis: co-conspirators or independent agents?

Forte

Bernardi

2006

Cell Death Differ

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The mitochondrial permeability transition from in vitro artifact to disease target

Cited by 600 publications

References 272 publications

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

The permeability transition pore in cell death

The permeability transition and BCL-2 family proteins in apoptosis: co-conspirators or independent agents?

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