Mitochondrial permeability transition (PT) is the phenomenon in which the mitochondrial inner membrane becomes permeable to various solutes and ions. When PT is induced by Ca (2+), cytochrome c is released from mitochondria into the cytosol where it then triggers subsequent steps of programmed cell death, apoptosis How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on experimentally measured residue-residue distances, we recently solved the first atomic model for Bax oligomeric pores at the membranes using computational approaches As cytochrome c release can be induced by mitochondrial membrane alteration and permeability transition (MPT), mice were treated with cyclosporin A, which specifically inhibits MPT Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions. The release of cytochrome-c from mitochondria to the cytosol, where it activates the caspase family of proteases is believed to be primary trigger leading to the onset of apoptosis Thus, the release of cytochrome c may occur via modulation of mitochondrial volume regardless of the mechanisms leading to the mitochondrial swelling. In contrast to MPT-dependent release of cytochrome c, under these circumstances the mitochondria remain intact and capable of maintaining their membrane potential. 2.4
. Ceramides did not permeabilize the mitochondrial outer membrane, and stimulated cytochrome c release only in the presence of digitonin Cytochrome c is released from mitochondria into the cytosol in cells undergoing apoptosis. The temporal relationship between cytochrome c release and loss of mitochondrial membrane potential was monitored by laser-scanning confocal microscopy in single living pheochromocytoma-6 cells undergoing apoptosis induced by staurosporine
Increased mitochondrial Ca2+ accumulation is a trigger for the release of cytochrome c from the mitochondrial intermembrane space into the cytosol where it can activate caspases and lead to apoptosis Further work showed that cytochrome c was released from Xenopus mitochondria in a process involving only a limited permeabilization of the outer membrane. 31 The limited degree of outer membrane. Here we report that in apoptosis of sympathetic neurons induced by NGF deprivation, cytochrome c is released from mitochondria in the absence of mitochondrial swelling. Moreover, we show that addition of NGF back to neurons rescued by Boc-aspartyl (Ome)-fluoromethylketone (BAF) leads to restoration of normal cytochrome c content by mitochondria Although mitochondrial membrane potential is unchanged in cells containing only 25% of the normal amount of CL, free cytochrome c (cyt. c) is detected in the intermembrane space and the mitochondria exhibit signs of reorganized cristae. However, the release of cyt. c from the mitochondria still requires apoptotic stimulation
In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology. Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation. During apoptosis in intact cells, cytochrome c translocation was similarly blocked by Bcl-2 but not by a. The release of cytochrome c from mitochondria, which is regulated by Bcl-2 family members and is considered to take place through voltage-dependent anion channels (VDACs) on the outer membranes of mitochondria, results in activation of effector caspases, such as caspase-3, which induce apoptosis This mechanism involves release of cytochrome c through an outer membrane pore or channel that does not require the mitochondrial permeability transition or mitochondrial swelling. Unlike mitochondria isolated from many other tissues, e.g. liver, brain can accumulate very little Ca 2+ in the absence of adenine nucleotides [16, 17] Cytochrome c is a soluble protein localized in the mitochondrial intermembrane space. Its classical function is to transfer electrons from the cytochrome bc 1 complex to cytochrome oxidase on the surface of the inner mitochondrial membrane. In the last decade, however, cytochrome c was also found to participate in the mechanisms that regulate apoptosis and became the hallmark of this type of.
The latter includes enhanced membrane permeability, fall in mitochondrial membrane potential (Deltapsi (m)) and release of cytochrome c into the cytosol. Gelsolin, an actin regulatory protein, has been shown to inhibit apoptosis, but when cleaved by caspase-3, a fragment that is implicated as an effector of apoptosis is generated Rather than inert passing of the cytochrome C through a rigid pore, the flexible pore may selectively aid the cytochrome C passage. Once the Bax pore is formed in the membrane, with a low energy barrier, the release of cytochrome C may be readily achieved through energy fluctuations
In valinomycin induced stimulation of mitochondrial energy dependent reversible swelling, supported by succinate oxidation, cytochrome c (cyto-c) and sulfite oxidase (Sox) [both present in the mitochondrial intermembrane space (MIS)] are released outside. This effect can be observed at a valinomycin concentration as low as 1 nM. The rate of cytosolic NADH/cyto-c electron transport pathway is. In mammalian apoptosis, the PTP can mediate mitochondrial outer membrane permeabilization (MOMP), which is suspected to be responsible for the release of apoptogenic factors, including cytochrome c. Although release of cytochrome c in yeast apoptosis has previously been reported, it is not known how it occurs The release of cytochrome c from the mitochondria to the cytosol is a critical step for downstream caspase-mediated apoptotic signal transduction in ischemia-reperfusion (I/R)-induced myocardial tissue injury. 10-N-nonyl acridine orange (NAO), a cardiolipin-specific dye, has been shown to inhibit Bid-mediated cytochrome c release from isolated mitochondria in vitro; however, the possible. , TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9
This finding indicated that the change in outer membrane permeability occurred upstream of the step affected by Bcl-2 activity or in an independent pathway. In Bcl-2-overexpressing cells, there was no release of cytochrome c from mitochondria, underlining the fact that the decrease in endogenous respiration is not dependent on cytochromec release Bax induces Cyt c release from isolated mitochondria. In A, mitochondria were incubated for 1 hr at 30°C with 1 μM Bax, 150 μM Ca 2+, both, or neither of these reagents. Mitochondria were then pelleted by centrifugation, and the resulting supernatants were subjected to SDS/PAGE immunoblot analysis by using an anti-Cyt c antibody Overexpression of ISG12b2 in Hepa 1-6 induced release of cytochrome c from mitochondria, disruption of the mitochondrial membrane potential, and activation of caspase-9, caspase-3, and caspase-8 .. q 2006 International Society for Analytical Cytology Cytometry Part A 69A:515-523 (2006) Method for Monitoring of Mitochondrial Cytochrome c Release During Cell Death: Immunodetection of Cytochrome c by Flow Cytometry After Selective Permeabilization of the Plasma Membrane Claudia B. L. Campos,1,2 Bruno A. Paim,1 Ricardo G. Cosso,1 Roger F. Castilho,1 Hagai Rottenberg,1 and Anibal E.
Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3 Hui Li,1 Siva Kumar Kolluri,1 Jian Gu,1 Marcia I. Dawson,2 Xihua Cao,1 Peter D. Hobbs,3 Bingzhen Lin,1 Guo-quen Chen,1 Jiang-song Lu,4 Feng Lin,1 Zhihua Xie,1 Joseph A. Fontana,4 John C. Reed,1 Xiao-kun Zhang1* TR3, an immediate-early response gene and an orphan member of the steroid The amount of CCR was compared with known quantities of cyto c standard. As shown in Fig. 1 F, the vast majority of mitochondrial cyto c was released to the cytosol in permeabilized cells exposed to X + XO (5 mU/ml) for 375 s. Thus, the loss of cyto c from mitochondria in response to O 2·− treatment is rapid and almost complete
Release of cytochrome c from mitochondria to cytosol was found after 12 h incubation with IFN-alpha, followed by a decline in mitochondrial membrane potential (Delta psi(m)) and procaspase-3 activation at 24 and 36 h, respectively Thus, release of cytochrome c could not be caused by rupturing the outer mitochondrial membrane due to matrix swelling. This conclusion holds true for apoptosis induced by various treatments including UV, TNF, actinomycin D and staurosporin Mitochondrial defects and heterogeneous cytochrome c release after cardiac cold ischemia and reperfusion Andrey V. Kuznetsov,1 Stefan Schneeberger,1 Ru¨diger Seiler,1 Gerald Brandacher,1 Walter Mark, 1 Wolfgang Steurer, 1 Valdur Saks,2 Yves Usson,3 Raimund Margreiter,1 and Erich Gnaiger1 1Department of Transplant Surgery, D. Swarovski Research Laboratory, University Hospital Innsbruck Conclusions—OxLDL induces dysfunction of the mitochondrial membrane, leading to cytochrome C release into the cytosol, and thereby stimulates apoptosis of human endothelial cells. Apoptosis suppression by CSA correlates with the prevention of mitochondrial dysfunction and thus indicates the importance of mitochondrial destabilization in oxLDL-induced apoptosis signaling MPT is caused by the opening of permeability transition pores in the inner mitochondrial membrane, leading to matrix swelling, outer membrane rupture, release of apoptotic signaling molecules such as cytochrome c from the intermembrane space, and irreversible injury to the mitochondria
The mechanism by which NO leads to cytochrome c release in the absence of changes of the mitochondrial transmembrane potential remains unexplained. It is possible that NO, in addition to the effects on the cytochrome c molecule, might act directly on proteins of the Bcl‐2 family (Bax, for example), the localization and function of which can be altered, as shown for Bax in other systems ( 26. Rather, the cytochrome C release induced by Bax is facilitated by Mg 2+ 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, Mg 2+ sensitive but cyclosporin insensitive
. A growing body of evidences indicate that oxidized cardiolipin rather than non‐oxidized cardiolipin is the real player in mitochondrial cytochrome c release [11, 13, 14, 19] Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors.
The mechanism during apoptosis by which cytochrome c is rapidly and completely released in the absence of mitochondrial swelling is uncertain. Here, we show that two distinct pathways are involved. One mediates release of cytochrome c across the outer mitochondrial membrane, and another, characterized in this study, is responsible for the redistribution of cytochrome c stored in. One of these factors is cytochrome c, a protein that normally shuttles electrons between protein complexes in the inner mitochondrial membrane. But once released, cytochrome c helps to activate.
cytochrome c release. Similarly, cytochrome c release in intact acinar cells (as well as caspase activation and apoptosis) is stimulated by Ca2+ and ROS, and inhibited by mitochondrial depolarisa-tion. The results indicate that death responses of pancreatitis are regulated at the mitochondrial level by the interplay between Ca2+, DYm and ROS. (MPT). MPT is caused by the opening of permeability transition pores in the inner mitochondrial membrane, leading to matrix swelling, outer membrane rupture, release of apoptotic signaling molecules such as cytochrome c from the intermembrane space, and irreversible injury to the mitochondria. During ischemia (the MPT priming phase), factor Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation Cecilia M.P. Rodrigues, Xiaoming Ma, Cheryle Linehan-Stieers, Guangsheng Fan, Betsy T. Kren, Clifford J Stee The mitochondrial Ca2+-independent phospholipase A2 is activated during energy-dependent Ca2+ accumulation under conditions where there is a sustained depression of the membrane potential. This activation is not dependent on induction of the mitochondrial permeability transition. Bromoenol lactone, which inhibits the phospholipase, is effective as an inhibitor of the transition, and this.
The latter includes enhanced membrane permeability, fall in mitochondrial membrane potential (Δψ m) and release of cytochrome c into the cytosol. Gelsolin, an actin regulatory protein, has been shown to inhibit apoptosis, but when cleaved by caspase-3, a fragment that is implicated as an effector of apoptosis is generated cruited to DISC, mitochondrial membrane depolarization (MMD) and release of cytochrome c precede activation of caspase-3. This release of cytochrome c may initiate the ex-ecution phase (8) by Apaf-1-mediated processing of pro-caspase-9 to active caspase-9, resulting in activation of caspase-3 (9, 10). Accordingly, inhibition of MMD and cy. . OPA1haplo-insufficiency is responsible for the most common form of autosomal dominant optic atrophy (ADOA, MIM165500), a neuropathy resulting from degeneration of the retinal ganglion cells and optic nerve atrophy The levels of BH3 peptide-induced cytochrome c release were dramatically reduced in the mitochondria isolated from the parkin-expressing SH-SY5Y cells, compared with the naïve SH-SY5Y control (Fig. 6A, lanes 8, 9 and 10), confirming the effect of parkin on mechanisms governing stimulated release of mitochondrial cytochrome c. Alamethicin and NP-40 confirmed equal mitochondrial purity and.
During apoptosis, cytochrome c is released into the cytosol as the outer membrane of mitochondria becomes permeable, and this acts to trigger caspase activation. The consequences of this release for mitochondrial metabolism are unclear It appears clearly that a large proportion of cytochrome c in Bax‐expressing cells is now released by nystatin, indicating its cytosolic localization. This release is very rapid, since only after 1 h of induction 50% of the cytochrome c is already in the cytosol (Fig. 4) First, the BH3-only Bax-interacting protein Bid, which is a substrate of caspase-8, becomes activated in the death receptor-mediated pathway and induces the release of cytochrome c from mitochondria.7,8Activated Bid triggers a conformational change of another proapoptotic molecule, Bax, which leads to its oligomerization and subsequent insertion into the outer mitochondrial membrane and finally to cytochrome c release.9,10 Second, caspase-9 can activate procaspase-8 via the caspase-3 and. Histones destabilize the mitochondrial membrane organization and cause release of cytochrome c A. Cascone, C. Bruelle, D. Lindholm, P. Bernardi, O. Eriksson ResearchProgramUnitandInstituteofBiomedicine,BiomedicumHelsinki1, University of Helsinki, FIN-00290 Helsinki, Finland MinervaFoundation,InstituteforMedical Research,BiomedicumHelsinki 2
separated cytochrome c release from the subsequent decrease in mitochondrial membrane potential (DW m). Cyt. c-GFP rescued respiration in cells lacking endogenous cytochrome c, and the duration of cytochrome c release was approximately 5min in a variety of cell types induced to die by various forms of cellular stress. In addition, we coul Bax, a member of the Bcl-2 protein family, is involved in controlling apoptotic events. High level of Bcl-2 inhibits apoptosis by preventing cytochrome release while high level of Bax induces apoptosis by binding to the mitochondrial membrane and increases membrane permeability allowing the release of cytochrome c [ 1
Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation. Cell Death and Differentiation, 1999. Clifford Steer. Betsy Kren. Cecília Rodrigues. Clifford Steer. Betsy Kren However, some studies have provided evidence that Cyt C release can occur independent of any detectable loss in mitochondrial Δψ m.2 Encouraged by our findings that C5 triggered the release of mitochondrial Cyt C in HL60 cells, we set out to investigate whether this cytosolic translocation of Cyt C resulted from a direct effect on mitochondrial membrane structures, specifically the MPT pore
Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J Neurochem 2002; 80: 207-218. Google Scholar 129. Heiskanen KM, Bhat MB, Wang H-W, Ma J, Nieminen AL. Mitochondrial depolarization accompanies cytochrome c release during apoptosis in PC6 cells Our results demonstrated that diazoxide or hypoxia, alone or in combination, could depolarize ΔΨmthrough opening mitoKATP, release of cytochrome C, and overproduction of hydrogen peroxide by mitochondria, resulting in increased proliferation and decreased apoptosis of hPASMCs Immediate effects of release of cytochrome c from the inner mitochondrial membrane, an event decreasing, as we suggest, the level of ROS; if, nevertheless, the ROS level increases, it causes apoptosis provided that caspase activation is possible. 2. Remote consequences of the respiratory chain inhibition due to cytochrome c release
One suggested mechanism for cytochrome c release involves the induction of the mitochondrial PTP (permeability transition pore), a large channel that spans both the OMM and IMM (inner mitochondrial membrane) [ 1, 10 ] Parl−/− mitochondria undergo faster apoptotic cristae remodeling and cytochrome c release. These findings implicate regulated intramembrane proteolysis in controlling apoptosis Previous results demonstrated that a synthetic BH3 peptide mimics the ability of the BH3-only protein Bid to promote Bax insertion and cytochrome c (cyt c ) release from neural cell mitochondria. However, the BH3 peptide was deficient in promoting cyt c release from mitochondria without associated Bax, such as adult rat brain mitochondria Cytochrome c Oxidase (CcO, Complex IV) is a large, membrane-bound dimeric enzyme, with each half of the dimer consisting of 13 protein chains. The complex acts as the terminus of mitochondrial electron transport in all aerobic life, by using four electrons to reduce dioxygen: O 2 + 4H + + 4e - ==> 2 H 2 O A Caspase-activated Factor (CAF) Induces Mitochondrial Membrane Depolarization and Cytochrome c Release by a Nonproteolytic Mechanism. Journal of Experimental Medicine, 1998. Vera Goossens. Download PDF. Download Full PDF Package. This paper. A short summary of this paper
We previously observed that caspase‐3 could induce cyt c release from isolated mitochondria from cultured IM‐9 cells, a multiple myeloma cell line. Using mitochondria isolated from mouse liver, we confirmed that recombinant caspase‐3‐induced release of cyt c from mitochondria was inhibited by z‐VAD.fmk mitochondria to induce cytochrome c release and found that recombinant caspase-3 induced opening of permeability transi-tion pore and reduction of membrane potential in vitro. These events were inhibited by Bcl-xL, cyclosporin A and z-VAD.fmk. Moreover, caspase-3 stimulated the rate of mitochondrial stat
It is suggested that mitochondrial‐induced ROS production promotes cytochrome c release from mitochondria by a two‐steps process, consisting of the dissociation of this protein from cardiolipin, followed by permeabilization of the outer membrane, probably by interaction with VDAC Lactate dehydrogenase (LDH) release from cultured cells was used as a measure of cell death. activity was measured by the reduction of cytochrome c at 550 nm, characterized by a progressive permeabilization of the inner mitochondrial membrane,.
cytochrome c release and mitochondrial respiratory inhibition. Reperfusion of hearts after 30 min ischemia further stimulated caspase activity membrane potential, when the latter was titrated with car-boxyatractyloside (0.4-8 nmol/mg mitochondrial protein) To examine whether OPA1 is required for the inhibition of cytochrome c release induced by MICS1 overexpression, OPA1 was knocked down in the MICS1-overexpressing cells. In control cells, apoptotic release of cytochrome c was stimulated by OPA1 RNAi as reported previously (Olichon et al., 2003; Lee et al., 2004)
Cytochrome c (Cyt c) levels in isolated mitochondria and mitoplasts of G93A-SOD1 brain. A, A representative Western blot experiment of inner mitochondrial membrane-associated cytochrome c detection, measured as a ratio to SDH [flavoprotein (Fp)] In addition, cytochrome c release from mitochondria isolated from GalN/LPS-treated rats was observed, and the release was inhibited by anti-MGST1 antibodies. Incubation of mitochondria from control rats with diamide and diamide plus GSH in vitro resulted in dimer- and mixed disulfide bond-mediated activation of mtMGST1, respectively Recent advancements in live cell imaging technologies have identified the phenomenon of intracellular propagation of late apoptotic events, such as cytochrome c release and caspase activation. The mechanism, prevalence, and speed of apoptosis propagation remain unclear. Additionally, no studies have demonstrated propagation of the pro-apoptotic protein, BAX Cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition pore (PTP), did not completely rescue HL-60 cells from apoptosis. Taken together, we conclude that TGHQ facilitates ROS production, alters the post-translational modification of Bcl-2 and subcellular localization of Bax, culminating in the release of cytochrome c and caspase activation
Cytochrome c significantly accumulated in the cytoplasm beginning at 12 h and up to 48 h after costimulation, while cytochrome c levels diminished in the mitochondrial fraction. These results suggested that costimulation with IFN γ and TNF α increased mitochondrial membrane permeability and induced cytochrome c release Cytochrome c peroxidase (CCP) is a nuclearly encoded hemoprotein located in the intermembrane space (IMS) of Saccharomyces cerevisiae mitochondria. Wild-type preCCP synthesized in rabbit reticulocyte lysates, however, was inefficiently translocated into isolated mitochondria and was inherently resistant to externally added proteases Disruption of the mitochondrial membrane potential is lethal to cells as they become bioenergetically deficient ( 25). Breakdown of the mitochondrial membrane potential in turn leads to release of cytochrome c into the cytosol and activation of caspase cascades that commits the cell to die by apoptosis ( 35)
Cell viability and mitochondrial functions, including mitochondrial membrane potential ( Δψ m), Cytochrome C release, mtDNA copy number, and mitochondrial biogenesis, were examined. Protein levels and SGK1 activation were significantly stimulated by H 2 O 2 exposure A proposed model of release of cleaved PGAM5 from mitochondria during mitophagy. PGAM5 is cleaved within the TM domain in response to loss of mitochondrial membrane potential (Δψ m) in the initial step of PINK1-Parkin-dependent mitophagy and released from mitochondria depending on proteasome-mediated rupture of the OMM Each value represents the mean SD (**denote cases where data are significantly different from control [0 hr time point], at p < 0.01, and * at p < 0.05 with Tukeys post hoc). - 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane. Cytochrome c release is a two-step process that is initiated by its dissociation from cardiolipin, which normally anchors cardiolipin in the inner mitochondrial membrane . Oxidation of cardiolipin during apoptosis reduces cytochrome c binding and increases the amount of free cytochrome c in the intermembrane space ( 5 , 6 )
and Bak induce apoptogenic mitochondrial cytochrome c release and membrane potential (Dc) loss in isolated mitochondria. Using isolated mitochondria, we showed that Bid and Bik, BH3-only proteins from the Bcl-2 family, induced cytochrome c release but not Dcloss. Unlike BaxyBak, the cytochrome c release induced b Mitochondrial dysfunction associated with apoptosis is characterized with the loss of mitochondrial membrane potential (ΔΨ m), permeability transition, and the release of cytochrome c from the mitochondria into the cytosol 
Release of cyt c from the mitochondrial intermembrane space to the cytosol occurs through the outer membrane. By forming an apoptosome complex with Apaf-1, pro-caspase-9 and ATP or dATP, the released cyt c ultimately triggers activation of downstream postmitochondrial caspases (caspase-3 and caspase-7) The latter includes enhanced membrane permeability, fall in mitochondrial membrane potential (Deltapsi(m)) and release of cytochrome c into the cytosol. Gelsolin, an actin regulatory protein, has been shown to inhibit apoptosis, but when cleaved by caspase-3, a fragment that is implicated as an effector of apoptosis is generated Black tea induces tumor cell apoptosis by Bax translocation, loss in mitochondrial transmembrane potential, cytochrome c release and caspase activation. International Journal of Cancer, 2005. Lakshmishri Lahiry. Tanya Das. Gaurisankar Sa. Arindam Bhattacharyya. Debaprasad Mandal
Each value represents the mean ± SD (*indicates statistically significant difference from control at p < 0.01 and þ represents statistically significant different between TGHQ and TGHQ/cyclosporin A co-treated groups at p < 0.05 with Tukey's post-hoc). - 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial. Journal of immunology (Baltimore, Md. : 1950) 1999-10-21 Granzyme B-induced loss of mitochondrial inner membrane potential (Delta Psi m) and cytochrome c release are caspase independent Inner and Outer Mitochondrial Membrane Disruption and Phosphatidylserine Externalization in Platelets. A key event in apoptotic cell death is the release of cytochrome c from the mitochondrial intermembrane space to the cytosol. 17 Controlled digitonin permeabilization of the plasma membrane can be used to examine retention of cytochrome c within the mitochondrial intermembrane space. 18. UDC and TUDC markedly reduced cytochrome c release associated with mitochondrial permeabilization induced by UCB and Aβ, respectively (p < 0.05). Moreover, cyclosporine A significantly inhibited mitochondrial swelling and cytochrome c efflux mediated by UCB (p < 0.05). UCB and Aβ peptide activate the apoptotic machinery in neural cells In conclusion, the present study suggests the existence of two mechanisms of mitochondrial cytochrome c release during stress-induced cell death: (1) passive cytochrome c release secondary to strong mitochondrial depolarization and matrix swelling that is not inhibited by Bcl-xL overexpression and that predominantly leads to cell necrosis and (2) active cytochrome c release that is inhibited.