The Release of Cytochrome c from Mitochondria during Apoptosis of NGF-deprived Sympathetic Neurons Is a Reversible Event

Martinou, Isabelle; Desagher, Solange; Eskes, Robert; Antonsson, Bruno; André, Élisabeth; Fakan, Stanislav; Martinou, Jean‐Claude

doi:10.1083/jcb.144.5.883

Cited by 278 publications

(221 citation statements)

References 50 publications

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“…Despite all the data implicating the PT-pore in cell death, a number of caveats have been raised against the PT-pore: Some investigators failed to see a dependence on the PT-pore for Bax-and Bid-induced apoptosis [16][17][18][19]. Also, in some apoptosis scenarios Bax-induced release of cytochrome c could not be inhibited by bongkrekic acid and or CsA [20].…”

Section: Evidence Against the Pt-pore In Cell Death And Modificationsmentioning

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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Section: Evidence Against the Pt-pore In Cell Death And Modificationsmentioning

confidence: 99%

The permeability transition pore in cell death

2007

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“…In many cell types mitochondrial membrane permeabilization (MMP) is considered as the point of nonreturn in the cell suicide (Ferri and Kroemer, 2001). However, in sympathetic neurons for example, this event appears to be reversible and death can be circumvented downstream of cytochromic c release (Martinou et al, 1999;Deshmukh et al, 2000;Tolkovsky et al, 2002). Whether it is also the case in cancer cells remains to be determined.…”

Section: Mitochondrial Membrane Permeabilizationmentioning

confidence: 99%

Mitochondria and cancer: is there a morphological connection?

2006

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Mitochondria are key players in several cellular functions including growth, division, energy metabolism, and apoptosis. The mitochondrial network undergoes constant remodelling and these morphological changes are of direct relevance for the role of this organelle in cell physiology. Mitochondrial dysfunction contributes to a number of human disorders and may aid cancer progression. Here, we summarize the recent contributions made in the field of mitochondrial dynamics and discuss their impact on our understanding of cell function and tumorigenesis.

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“…Because OPA1 appears to be required for the integrity of mitochondrial cristae and also for normal mitochondrial morphology, this raises the possibility that apoptosis-associated release of OPA1 into the cytosol underpins the extensive fragmentation of the mitochondrial network that is frequently observed during this mode of cell death. [15][16][17] Whereas the latter proposal remains speculative, it does seem that OPA1 serves an indispensable role in organizing mitochondrial cristae into their correct form and that interference with the function of this protein results in an increased potential for cytochrome c escape.…”

Section: Opa1 Regulates Mitochondrial Cristae Integritymentioning

confidence: 99%

“…2 Although it is clear that extensive mitochondrial fission is associated with apoptosis, [15][16][17] it remains a matter of debate as to whether this phenomenon also contributes to cytochrome c efflux. Although initial studies from Youle's laboratory suggested that interfering with the process of mitochondrial fission could delay the release of cytochrome c and consequent apoptosis, 20 subsequent reports suggest that these events may be coincident rather than functionally interconnected.…”

Section: Mitochondrial Fission and Apoptosismentioning

confidence: 99%