scholarly journals Mitochondrial cytochrome c release may occur by volume-dependent mechanisms not involving permeability transition

2004 ◽  
Vol 378 (1) ◽  
pp. 213-217 ◽  
Author(s):  
Vladimir GOGVADZE ◽  
John D. ROBERTSON ◽  
Mari ENOKSSON ◽  
Boris ZHIVOTOVSKY ◽  
Sten ORRENIUS
Keyword(s):  
Cytochrome C ◽  
In Vitro Model ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Outer Membrane ◽  
Cytochrome C Release ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Mitochondrial Volume ◽  
Vitro Model

The mechanisms regulating mitochondrial outer-membrane permeabilization and the release of cytochrome c during apoptosis remain controversial. In the present study, we show in an in vitro model system that the release of cytochrome c may occur via moderate modulation of mitochondrial volume, irrespective of the mechanism leading to the mitochondrial swelling. In contrast with mitochondrial permeability transition-dependent release of cytochrome c, in the present study mitochondria remain intact and functionally active.

scholarly journals Requirement of Apaf-1 for mitochondrial events and the cleavage or activation of all procaspases during genotoxic stress-induced apoptosis

2007 ◽  
Vol 405 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Emily E. Franklin ◽  
John D. Robertson
Keyword(s):  
Cytochrome C ◽  
Genotoxic Stress ◽  
Jurkat Cells ◽  
Mitochondrial Outer Membrane ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Caspase 2 ◽  
Induced Apoptosis

Sequential activation of caspases is critical for the execution of apoptosis. Recent evidence suggests caspase 2 is a significant upstream caspase capable of initiating mitochondrial events, such as the release of cytochrome c. In particular, in vitro studies using recombinant proteins have shown that cleaved caspase 2 can induce mitochondrial outer membrane permeabilization directly or by cleaving the BH3-only protein BID (BH3 interacting domain death agonist). However, whether interchain cleavage or activation of procaspase 2 occurs prior to Apaf-1-mediated procaspase 9 activation under more natural conditions remains unresolved. In the present study, we show that Apaf-1-deficient Jurkat T-lymphocytes and mouse embryonic fibroblasts were highly resistant to DNA-damage-induced apoptosis and failed to cleave or activate any apoptotic procaspase, including caspase 2. Significantly, drug-induced cytochrome c release and loss of mitochondrial membrane potential were inhibited in cells lacking Apaf-1. By comparison, procaspase proteolysis and apoptosis were only delayed slightly in Apaf-1-deficient Jurkat cells upon treatment with anti-Fas antibody. Our data support a model in which Apaf-1 is necessary for the cleavage or activation of all procaspases and the promotion of mitochondrial apoptotic events induced by genotoxic drugs.

scholarly journals VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release

2001 ◽  
Vol 155 (6) ◽  
pp. 1003-1016 ◽  
Author(s):  
Muniswamy Madesh ◽  
György Hajnóczky
Keyword(s):  
Cytochrome C ◽  
Hepg2 Cells ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Anion Channel ◽  
Permeability Transition ◽  
Mitochondrial Outer Membrane ◽  
Inner Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Cytochrome C Release

Enhanced formation of reactive oxygen species (ROS), superoxide (O2·−), and hydrogen peroxide (H2O2) may result in either apoptosis or other forms of cell death. Here, we studied the mechanisms underlying activation of the apoptotic machinery by ROS. Exposure of permeabilized HepG2 cells to O2·− elicited rapid and massive cytochrome c release (CCR), whereas H2O2 failed to induce any release. Both O2·− and H2O2 promoted activation of the mitochondrial permeability transition pore by Ca2+, but Ca2+-dependent pore opening was not required for O2·−-induced CCR. Furthermore, O2·− alone evoked CCR without damage of the inner mitochondrial membrane barrier, as mitochondrial membrane potential was sustained in the presence of extramitochondrial ATP. Strikingly, pretreatment of the cells with drugs or an antibody, which block the voltage-dependent anion channel (VDAC), prevented O2·−-induced CCR. Furthermore, VDAC-reconstituted liposomes permeated cytochrome c after O2·− exposure, and this release was prevented by VDAC blocker. The proapoptotic protein, Bak, was not detected in HepG2 cells and O2·−-induced CCR did not depend on Bax translocation to mitochondria. O2·−-induced CCR was followed by caspase activation and execution of apoptosis. Thus, O2·− triggers apoptosis via VDAC-dependent permeabilization of the mitochondrial outer membrane without apparent contribution of proapoptotic Bcl-2 family proteins.

scholarly journals In vitro and in vivo effect of 3-Para-fluorobenzoyl-propionic acid on rat liver mitochondrial permeability transition pore opening and lipid peroxidation

2020 ◽  
Vol 5 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Adeola O. Olowofolahan ◽  
Omosola L. Bolarin ◽  
Olufunso O. Olorunsogo
Keyword(s):  
Lipid Peroxidation ◽  
Cytochrome C ◽  
Propionic Acid ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Atpase ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Pore Opening

AbstractThe opening of mitochondrial permeability transition (mPT) pore is a well recognized important event in the execution of mitochondrial-mediated apoptosis. Some bioactive compounds induce apoptosis in tumour cells via the induction of mPT pore opening. This study therefore investigated the effect of 3-Para-fluorobenzoyl-propionic acid (3PFBPA), a metabolite of haloperidol on mPT pore, mitochondrial ATPase activity (mATPase), mitochondrial lipid peroxidation (mLPO) and cytochrome c release (CCR). Thirty-two male Wistar rats, were acclimatized for 14 days in clean cages. After 30 days of treatment, they were sacrificed and the liver mitochondria isolated using differential centrifugation. The mPT pore, mATPase, mLPO and CCR were determined by standard methods using a spectrophotometer. The mPT pore opening was induced by 3PFBPA by 1.4, 3.6, 5.6, 6.6 and 7.4 folds, when compared with the control. Also, there was release of cytochrome c and enhancement of mATPase activity by 3PFBPA. The results also show that 3PFBPA reduced lipid peroxidation. However, oral administration of 3PFBPA at 50, 100 and 200 mg/kg did not have any effect on mPT pore opening and mATPase activity when compared with the control but there was inhibition of mLPO. These findings suggested the pharmacological potential of 3PFBPA against the pathological processes related to insufficient apoptosis (based on the in vitro data) and oxidative stress due to its anti-lipidperoxidative effect.

Effect of chronic contractile activity on SS and IMF mitochondrial apoptotic susceptibility in skeletal muscle

2007 ◽  
Vol 292 (3) ◽  
pp. E748-E755 ◽  
Author(s):  
Peter J. Adhihetty ◽  
Vladimir Ljubicic ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Manganese Superoxide Dismutase ◽  
Mitochondrial Permeability Transition ◽  
Contractile Activity ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Production ◽  
Cytochrome C Release ◽  
Apoptosis Inducing Factor

Chronic contractile activity of skeletal muscle induces an increase in mitochondria located in proximity to the sarcolemma [subsarcolemmal (SS)] and in mitochondria interspersed between the myofibrils [intermyofibrillar (IMF)]. These are energetically favorable metabolic adaptations, but because mitochondria are also involved in apoptosis, we investigated the effect of chronic contractile activity on mitochondrially mediated apoptotic signaling in muscle. We hypothesized that chronic contractile activity would provide protection against mitochondrially mediated apoptosis despite an elevation in the expression of proapoptotic proteins. To induce mitochondrial biogenesis, we chronically stimulated (10 Hz; 3 h/day) rat muscle for 7 days. Chronic contractile activity did not alter the Bax/Bcl-2 ratio, an index of apoptotic susceptibility, and did not affect manganese superoxide dismutase levels. However, contractile activity increased antiapoptotic 70-kDa heat shock protein and apoptosis repressor with a caspase recruitment domain by 1.3- and 1.4-fold ( P < 0.05), respectively. Contractile activity elevated SS mitochondrial reactive oxygen species (ROS) production 1.4- and 1.9-fold ( P < 0.05) during states IV and III respiration, respectively, whereas IMF mitochondrial state IV ROS production was suppressed by 28% ( P < 0.05) and was unaffected during state III respiration. Following stimulation, exogenous ROS treatment produced less cytochrome c release (25–40%) from SS and IMF mitochondria, and also reduced apoptosis-inducing factor release (≈30%) from IMF mitochondria, despite higher inherent cytochrome c and apoptosis-inducing factor expression. Chronic contractile activity did not alter mitochondrial permeability transition pore (mtPTP) components in either subfraction. However, SS mitochondria exhibited a significant increase in the time to Vmax of mtPTP opening. Thus, chronic contractile activity induces predominantly antiapoptotic adaptations in both mitochondrial subfractions. Our data suggest the possibility that chronic contractile activity can exert a protective effect on mitochondrially mediated apoptosis in muscle.

scholarly journals Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study

2004 ◽  
Vol 382 (3) ◽  
pp. 877-884 ◽  
Author(s):  
Bruno GUIGAS ◽  
Dominique DETAILLE ◽  
Christiane CHAUVIN ◽  
Cécile BATANDIER ◽  
Frédéric De OLIVEIRA ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Intact Cells ◽  
Human Carcinoma ◽  
Butyl Hydroperoxide ◽  
Mitochondrial Permeability ◽  
New Findings

Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.

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

1998 ◽  
Vol 143 (1) ◽  
pp. 217-224 ◽  
Author(s):  
Robert Eskes ◽  
Bruno Antonsson ◽  
Astrid Osen-Sand ◽  
Sylvie Montessuit ◽  
Christoph Richter ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
Mammalian Homologue

Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A–sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.

Sign in / Sign up

Export Citation Format

Share Document