Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions

Eskes, Robert; Antonsson, Bruno; Osen-Sand, Astrid; Montessuit, Sylvie; Richter, Christoph; Sadoul, Rémy; Mazzei, Gonzalo J.; Nichols, Anthony; Martinou, Jean‐Claude

doi:10.1083/jcb.143.1.217

Cited by 604 publications

(477 citation statements)

References 41 publications

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“…m CRITICAL STEP The use of EDTA instead of EGTA chelates also Mg 2+ , which is extremely abundant in muscle tissue (given the high content in ATP). Mg 2+ can influence mitochondrial function as well as the kinetics of cytochrome c release 25 . (ii) Mince the muscles into small pieces using scissors and trim visible fat, ligaments and connective tissue.…”

Section: Methodsmentioning

confidence: 99%

Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts

2007

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Section: Methodsmentioning

confidence: 99%

Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts

2007

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“…AIF has recently been reported to induce apoptotic nuclear changes in a caspase-independent manner after translocation into the nucleus (Susin et al, 1999). We and others have shown that pro-apoptotic Bcl-2 family members (Bax, Bak, Bid, and Bik) induce apoptotic changes in isolated mitochondria that are prevented by Bcl-2 and Bcl-x L (JuÈ rgensmeier et al, 1998;Narita et al, 1998;Eskes et al, 1998;Shimizu and Tsujimoto, 2000). Although there seems to be controversy, it has been shown that Bax-and Bak-induced mitochondrial changes are mediated by a polyprotein channel called the permeability transition (PT) pore (Narita et al, 1998;Marzo et al, 1998), which is considered to form at sites of contact between the mitochondrial inner and outer membranes and to consist of mitochondrial porin (also called the voltage-dependent anion channel, VDAC), the adenine nucleotide translocator (ANT), cyclophilin D, and some other molecules (reviewed by Bernardi et al, 1994;Zoratti and SzaboÂ , 1995).…”

Section: Introductionmentioning

confidence: 90%

Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator

2000

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Mitochondria play an essential role in apoptosis by releasing apoptogenic molecules such as cytochrome c and AIF, and some caspases, which are all regulated by Bcl-2 family proteins. Pro-apoptotic Bax and Bak have been shown to induce cytochrome c release and loss of membrane potential (Dc) leading to AIF release in the isolated mitochondria. We have previously shown that Bax and Bak open the voltage-dependent anion channel (VDAC) allowing cytochrome c to pass through the channel, and Bcl-x L closes the channel. However, it has been reported that it is adenine nucleotide translocator (ANT) with which Bax/Bcl-x L interacts that modulate the channel activity. Here, we investigated the role of ANT and VDAC in the changes of isolated mitochondria triggered by Bax and by chemicals that induce permeability transition (PT). In rat and yeast mitochondria, Bax did not a ect the ADP/ATP exchange activity of ANT. VDAC-de®cient but not ANT-de®cient yeast mitochondria showed resistance to cytochrome c release, Dc loss, and swelling caused by Bax and PT inducers. Bcl-x L showed similar inhibition of all these changes in ANTde®cient and wild type yeast mitochondria. Furthermore, Bax induces cytochrome c release in wild type yeast cells but not VDAC1-de®cient yeast cells. These data indicate that VDAC, but not ANT, is essential for apoptotic mitochondrial changes. The data also indicate that Bcl-x L and Bax possess an ability to regulate mitochondrial membrane permeability independently of other Bcl-2 family members.

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“…Also, in some apoptosis scenarios Bax-induced release of cytochrome c could not be inhibited by bongkrekic acid and or CsA [20]. Of note, while both Bax and t-Bid bind to cardiolipin in the contact sites, they have different modes of action.…”

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

confidence: 96%

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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Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions

Cited by 604 publications

References 41 publications

Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts

Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts

Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator

The permeability transition pore in cell death

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