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1.
mCICR is required for As2O3-induced permeability transition pore opening and cytochrome c release from mitochondria 总被引:1,自引:0,他引:1
The permeability transition pore (PTP) is central for apoptosis by acting as a good candidate pathway for the release of Cyt. c and apoptosis induction factors (AIF). Arsenite induces apoptosis via a direct effect on PTP. To characterize the exact mechanism for arsenite induces PTP opening, the effect of Ca2+ on As2O3-induced PTP opening, the relationship between As2O3-induced PTP opening and Cyt. c release from mitochondria and calcium-induced calcium release from mitochondria (mCICR), and the effects of As2O3 on Ca2+-induced PTP opening were studied. The results showed As2O3 induces Cyt. c release by triggering PTP opening. Ca2+ is necessary for As2O3-induced PTP opening. As2O3-induced PTP opening and Cyt. c release depends on mCICR. As2O3 promotes PTP opening by lowering Ca2+-threshold. These results indicated As2O3 induce Cyt. c release from mitochondria by lowering Ca2+-threshold for PTP and triggering mCICR-dependent PTP opening. Suggesting that it is possible to control apoptosis by altering Ca2+ threshold and mCICR to modulate PTP opening and Cyt. c release. 相似文献
2.
辑 《中国科学:生命科学英文版》2000,43(5):489-497
The relationship between mitochondrial Ca2+ transport and permeability transition pore (PTP) opening as well as the effects of mitochondrial energetic status on mitochondrial Ca2+ transport and PTP opening were studied. The results showed that the calcium-induced calcium release from mitochondria (mCICR) induced PTP opening. Inhibitors for electron transport of respiratory chain inhibited mCICR and PTP opening. Partial recovery of electron transport in respiratory chain resulted in partial recovery of mCICR and PTP opening. mCICR and PTP opening were also inhibited by CCCP which eliminated transmembrane proton gradient. The results indicated that mitochondrial Ca2+ transport and PTP opening are largely dependent on electron transport and energy coupling. 相似文献
3.
The relationship between mitochondrial Ca2+ transport and permeability transition pore (PTP) opening as well as the effects of mitochondrial energetic status on mitochondrial Ca2+ transport and PTP opening were studied. The results showed that the calcium-induced calcium release from mitochondria (mCICR) induced PTP opening. Inhibitors for electron transport of respiratory chain inhibited mCICR and PTP opening. Partial recovery of electron transport in respiratory chain resulted in partial recovery of mCICR and PTP opening. mCICR and PTP opening were also inhibited by CCCP which eliminated transmembrane proton gradient. The results indicated that mitochondrial Ca2+ transport and PTP opening are largely dependent on electron transport and energy coupling. 相似文献
4.
Resveratrol, a natural polyphenolic antioxidant, has been reported to possess the cancer chemopreventive potential in wide
range by means of triggering tumor cells apoptosis through various pathways. It induced apoptosis through the activation of
the mitochondrial pathway in some kinds of cells. In the present reports, we showed that resveratrol-induced HepG2 cell apoptosis
and mitochondrial dysfunction was dependent on the induction of the mitochondrial permeability transition (MPT), because resveratrol
caused the collapse of the mitochondrial membrane potential (ΔΨm) with the concomitant release of cytochrome c (Cyt.c). In addition, resveratrol induced a rapid and sustained elevation of
intracellular [Ca2+], which compromised the mitochondrial ΔΨm and triggered the process of HepG2 cell apoptosis. In permeabilized HepG2 cells, we further demonstrated that the effect
of the resveratrol was indeed synergistic with that of Ca2+ and Ca2+ is necessary for resveratrol-induced MPT opening. Calcium-induced calcium release from mitochondria (mCICR) played a key
role in mitochondrial dysfunction and cell apoptosis: (1) mCICR inhibitor, ruthenium red (RR), prevent MPT opening and Cyt.c
release; and (2) RR attenuated resveratrol-induced HepG2 cell apoptotic death. Furthermore, resveratrol promotes MPT opening
by lowering Ca2+-threshold. These data suggest modifying mCICR and Ca2+ threshold to modulate MPT opening may be a potential target to control cell apoptosis induced by resveratrol.
Xuemei Tian—Foundation item: Chinese National Natural Science Foundation (No.30300455). 相似文献
5.
Modulation of cell calcium signals by mitochondria 总被引:4,自引:0,他引:4
Jouaville Laurence S. Ichas François Mazat Jean-Pierre 《Molecular and cellular biochemistry》1998,184(1-2):371-376
It is now clearer and clearer that mitochondria play a role, and perhaps an active role, in cell calcium signalling. The fact that mitochondria can exhibit a Ca2+>-induced Ca2+> release (mCICR, Ichas et al. [37]) reinforces this concept and makes the mitochondria an essential element in the relay of Ca2+> wave propagation. It must be emphasized that the modulation of cell Ca2+> signals by mitochondria depends upon their energetic status, thus making mitochondria an essential link between energy metabolism and calcium signalling inside the cell. 相似文献
6.
In order to explore the role of mitochondria in proliferation promotion and/or apoptosis induction of lanthanum, the mutual
influences between La3+ and Ca2+ on mitochondrial permeability transition pore (PTP) opening were investigated with isolated mitochondria from rat liver.
The experimental results revealed that La3+ influence the state of mitochondria in a concentration-dependent biphasic manner. La3+ in nanomolar concentrations, acting as a Ca2+ analog, entered mitochondrial matrix via the RuR sensitive Ca2+ channel and elevated ROS level, leading to opening of PTP indicated by mitochondrial swelling, reduction of ΔΨm and cytochrome c release. Inhibition of PTP with 10 μM CsA attenuated the effects of La3+. However, micromolar concentrations La3+ acted mainly as a Ca2+ antagonist, inhibiting PTP opening induced by Ca2+. We postulated that this action of La3+ on mitochondria through interaction with Ca2+ might be involved in the proliferation-promoting and apoptosis induction by La3+. 相似文献
7.
Cezar R. Pestana Carlos H. T. P. Silva Sérgio A. Uyemura Antonio C. Santos Carlos Curti 《Journal of bioenergetics and biomembranes》2010,42(4):329-335
Mitochondrial membrane carriers containing proline and cysteine, such as adenine nucleotide translocase (ANT), are potential
targets of cyclophilin D (CyP-D) and potential Ca2+-induced permeability transition pore (PTP) components or regulators; CyP-D, a mitochondrial peptidyl-prolyl cis-trans isomerase, is the probable target of the PTP inhibitor cyclosporine A (CsA). In the present study, the impact of proline
isomerization (from trans to cis) on the mitochondrial membrane carriers containing proline and cysteine was addressed using ANT as model. For this purpose,
two different approaches were used: (i) Molecular dynamic (MD) analysis of ANT-Cys56 relative mobility and (ii) light scattering techniques employing rat liver isolated mitochondria to assess both Ca2+-induced ANT conformational change and mitochondrial swelling. ANT-Pro61 isomerization increased ANT-Cys56 relative mobility and, moreover, desensitized ANT to the prevention of this effect by ADP. In addition, Ca2+ induced ANT “c” conformation and opened PTP; while the first effect was fully inhibited, the second was only attenuated by
CsA or ADP. Atractyloside (ATR), in turn, stabilized Ca2+-induced ANT “c” conformation, rendering the ANT conformational change and PTP opening less sensitive to the inhibition by
CsA or ADP. These results suggest that Ca2+ induces the ANT “c” conformation, apparently associated with PTP opening, but requires the CyP-D peptidyl-prolyl cis-trans isomerase activity for sustaining both effects. 相似文献
8.
O. V. Krestinina D. E. Grachev I. V. Odinokova G. Reiser Yu. V. Evtodienko T. S. Azarashvili 《Biochemistry. Biokhimii?a》2009,74(4):421-429
The effect of nanomolar concentrations of PBR/TSPO ligands—Ro 5-4864, PK11195, and PPIX—on Ca2+-induced permeability transition pore (PTP) opening in isolated rat brain mitochondria was investigated. PBR/TSPO agonist Ro 5-4864 (100 nM) and endogenous ligand PPIX (1 μM) were shown to stimulate PTP opening, while antagonist PK11195 (100 nM) suppressed this process. Correlation between PBR ligand action on PTP opening and phosphorylation of a 3.5 kDa polypeptide was investigated. In intact brain mitochondria, incorporation of [γ-32P]ATP into 3.5 kDa peptide was decreased in the presence of Ro 5-4864 and PPIX and increased in the presence of PK11195. At threshold Ca2+ concentrations leading to PTP opening, PBR/TSPO ligands were found to stimulate dephosphorylation of the 3.5 kDa peptide. Specific anti-PBR/TSPO antibody prevented both PTP opening and dephosphorylation of the 3.5-kDa peptide. The peptide was identified as subunit c of FoF1-ATPase by Western blot using specific anti-subunit c antibody. The results suggest that subunit c of FoF1-ATPase could be an additional target for PBR/TSPO ligands action, is subjected to Ca2+- and TSPO-dependent phosphorylation/dephosphorylation, and is involved in PTP operation in mitochondria. 相似文献
9.
Oxidative stress promotes Ca2+-dependent opening of the mitochondrial inner membrane permeability transition pore (PTP), causing bioenergetic failure and
subsequent cell death in many paradigms, including those related to acute brain injury. One approach to pre-conditioning against
oxidative stress is pharmacologic activation of the Nrf2/ARE pathway of antioxidant gene expression by agents such as sulforaphane
(SFP). This study tested the hypothesis that administration of SFP to normal rats increases resistance of isolated brain mitochondria
to redox-sensitive PTP opening. SFP or DMSO vehicle was administered intraperitoneally to adult male rats at 10 mg/kg 40 h
prior to isolation of non-synaptic brain mitochondria. Mitochondria were suspended in medium containing a respiratory substrate
and were exposed to an addition of Ca2+ below the threshold for PTP opening. Subsequent addition of tert-butyl hydroperoxide (tBOOH) resulted in a cyclosporin A-inhibitable release of accumulated Ca2+ into the medium, as monitored by an increase in fluorescence of Calcium Green 5N within the medium, and was preceded by a
decrease in the autofluorescence of mitochondrial NAD(P)H. SFP treatment significantly reduced the rate of tBOOH-induced Ca2+ release but did not affect NAD(P)H oxidation or inhibit PTP opening induced by the addition of phenylarsine oxide, a direct
sulfhydryl oxidizing agent. SFP treatment had no effect on respiration by brain mitochondria and had no effect on PTP opening
or respiration when added directly to isolated mitochondria. We conclude that SFP confers resistance of brain mitochondria
to redox-regulated PTP opening, which could contribute to neuroprotection observed with SFP. 相似文献
10.
Gyrgy Hajnczky Gyrgy Csords Sudipto Das Cecilia Garcia-Perez Masao Saotome Soumya Sinha Roy Muqing Yi 《Cell calcium》2006,40(5-6):553
Local Ca2+ transfer between adjoining domains of the sarcoendoplasmic reticulum (ER/SR) and mitochondria allows ER/SR Ca2+ release to activate mitochondrial Ca2+ uptake and to evoke a matrix [Ca2+] ([Ca2+]m) rise. [Ca2+]m exerts control on several steps of energy metabolism to synchronize ATP generation with cell function. However, calcium signal propagation to the mitochondria may also ignite a cell death program through opening of the permeability transition pore (PTP). This occurs when the Ca2+ release from the ER/SR is enhanced or is coincident with sensitization of the PTP. Recent studies have shown that several pro-apoptotic factors, including members of the Bcl-2 family proteins and reactive oxygen species (ROS) regulate the Ca2+ sensitivity of both the Ca2+ release channels in the ER and the PTP in the mitochondria. To test the relevance of the mitochondrial Ca2+ accumulation in various apoptotic paradigms, methods are available for buffering of [Ca2+], for dissipation of the driving force of the mitochondrial Ca2+ uptake and for inhibition of the mitochondrial Ca2+ transport mechanisms. However, in intact cells, the efficacy and the specificity of these approaches have to be established. Here we discuss mechanisms that recruit the mitochondrial calcium signal to a pro-apoptotic cascade and the approaches available for assessment of the relevance of the mitochondrial Ca2+ handling in apoptosis. We also present a systematic evaluation of the effect of ruthenium red and Ru360, two inhibitors of mitochondrial Ca2+ uptake on cytosolic [Ca2+] and [Ca2+]m in intact cultured cells. 相似文献
11.
Sophia von Stockum Valentina Giorgio Elena Trevisan Giovanna Lippe Gary D. Glick Michael A. Forte Caterina Da-Rè Vanessa Checchetto Gabriella Mazzotta Rodolfo Costa Ildikò Szabò Paolo Bernardi 《The Journal of biological chemistry》2015,290(8):4537-4544
Mitochondria of Drosophila melanogaster undergo Ca2+-induced Ca2+ release through a putative channel (mCrC) that has several regulatory features of the permeability transition pore (PTP). The PTP is an inner membrane channel that forms from F-ATPase, possessing a conductance of 500 picosiemens (pS) in mammals and of 300 pS in yeast. In contrast to the PTP, the mCrC of Drosophila is not permeable to sucrose and appears to be selective for Ca2+ and H+. We show (i) that like the PTP, the mCrC is affected by the sense of rotation of F-ATPase, by Bz-423, and by Mg2+/ADP; (ii) that expression of human cyclophilin D in mitochondria of Drosophila S2R+ cells sensitizes the mCrC to Ca2+ but does not increase its apparent size; and (iii) that purified dimers of D. melanogaster F-ATPase reconstituted into lipid bilayers form 53-pS channels activated by Ca2+ and thiol oxidants and inhibited by Mg2+/γ-imino ATP. These findings indicate that the mCrC is the PTP of D. melanogaster and that the signature conductance of F-ATPase channels depends on unique structural features that may underscore specific roles in different species. 相似文献
12.
Cytochrome c release and mitochondrial permeability transition (MPT) play important roles in apoptosis. In this study, we found that selenium, an essential trace element, induced mitochondrial membrane potential (Delta psi(m)) loss, swelling, and cytochrome c release in isolated mitochondria. All of the above observations were blocked by cyclosporin A (CsA), which is a specific inhibitor to permeability transition pore (PTP), indicating selenite-induced mitochondrial changes were mediated through the opening of PTP. In physiological concentration, selenite could induce mitochondria at low-conductance PTP 'open' probability, which is correlated to regulate the physiological function, whereas in toxic concentration, induce mitochondria at high-conductance PTP 'open' probability and rapidly undergo a process of osmotic swelling following diffusion toward matrix as for inducer (Ca(2+)/P(i)). Selenite also induced other mitochondrial marker enzymes including monoamine oxidase (MAO) and mitochondria aspartate aminotransferase (mAST). Oligomycin inhibited the selenite-induced cytochrome c release and Delta psi(m) loss, showing that F(0)F(1)-ATPase was important in selenite or Ca(2+)/P(i)-induced MPT. 相似文献
13.
The effect of Ca2+ applied in high concentrations (50 and 300 µM) was addressed on the generation of reactive oxygen species in isolated mitochondria from guinea-pig brain. The experiments were performed in the presence of ADP, a very effective inhibitor of mitochondrial permeability transition. Moderate increase in H2O2 release from mitochondria was induced by Ca2+ applied in 50 µM, but not in 300 µM concentration as measured with Amplex red fluorescent assay starting with a delay of 100-150 sec after exposure to Ca2+. Parallel measurements of membrane potential (ΔΨm) by safranine fluorescence showed a transient depolarization by Ca2+ followed by the recovery of ΔΨm to a value, which was more negative than that observed before addition of Ca2+ indicating a relative hyperpolarization. NAD(P)H fluorescence was also increased by Ca2+ given in 50 µM concentration. In mitochondria having high ΔΨm in the presence of oligomycin or ATP, the basal rate of release of H2O2 was significantly higher than that observed in a medium containing ADP and Ca2+ no longer increased but rather decreased the rate of H2O2 release. With 300 µM Ca2+ only a loss but no tendency of a recovery of ΔΨm was detected and H2O2 release was unchanged. It is suggested that in the presence of nucleotides the effect of Ca2+ on mitochondrial ROS release is related to changes in ΔΨm; in depolarized mitochondria, in the presence of ADP, moderate increase in H2O2 release is induced by calcium, but only in ≤ 100 µM concentration, when after a transient Ca2+-induced depolarization mitochondria became more polarized. In highly polarized mitochondria, in the presence of ATP or oligomycin, where no hyperpolarization follows the Ca2+-induced depolarization, Ca2+ fails to stimulate mitochondrial ROS generation. These effects of calcium (≤ 300 µM) are unrelated to mitochondrial permeability transition. 相似文献
14.
Exposure of mitochondria to oxidative stress and elevated Ca2+ promotes opening of the mitochondrial permeability transition pore (PTP), resulting in membrane depolarization, uncoupling of oxidative phosphorylation, and potentially cell death. This study tested the hypothesis that treatment of rats with sulforaphane (SFP), an activator of the Nrf2 pathway of antioxidant gene expression, increases the resistance of liver mitochondria to redox-regulated PTP opening and elevates mitochondrial levels of antioxidants. Rats were injected with SFP or drug vehicle and liver mitochondria were isolated 40 h later. Respiring mitochondria actively accumulated added Ca2+, which was then released through PTP opening induced by agents that either cause an oxidized shift in the mitochondrial redox state or directly oxidize protein thiol groups. SFP treatment of rats inhibited the rate of pro-oxidant-induced mitochondrial Ca2+ release and increased expression of the glutathione peroxidase/reductase system, thioredoxin, and malic enzyme. These results are the first to demonstrate that SFP treatment of animals increases liver mitochondrial antioxidant defenses and inhibits redox-sensitive PTP opening. This novel form of preconditioning could protect against a variety of pathologies that include oxidative stress and mitochondrial dysfunction in their etiologies. 相似文献
15.
Konstantin N. Belosludtsev Nils-Erik L. Saris Natalia V. Belosludtseva Alexander S. Trudovishnikov Lyudmila D. Lukyanova Galina D. Mironova 《Journal of bioenergetics and biomembranes》2009,41(4):395-401
Earlier we found that being added to rat liver mitochondria, palmitic acid (Pal) plus Ca2+ opened a cyclosporin A-insensitive pore, which remained open for a short time. Apparently, this pore is involved in the Pal-induced
apoptosis and may also take part in the mitochondrial Ca2+ recycling as a Ca2+ efflux system (Belosludtsev et al. J Bioenerg Biomembr 38:113–120, 2006; Mironova et al. J. Bioenerg. Biomembr. 39:167–174, 2007). In this paper, we continue studying physiological and regulatory aspects of the pore. The following observations have been
made. (1) Cardiolipin has been found to facilitate the Ca2+-induced formation of pores in the Pal-containing liposomal membranes. (2) The opening of Pal/Ca2+-induced pore is accompanied by the release of apoptosis-induced factor (AIF) from mitochondria. (3) The rate of Pal/Ca2+-induced swelling of rat liver mitochondria increases substantially with the age of animals. (4) Although the Pal/Ca2+-induced pore opens both in the liver and heart mitochondria, the latter require higher Pal concentrations for the pore to
open. (5) The pore opening depends on the resistance of animals to hypoxia: in the highly resistant to hypoxia rats, the mitochondrial
Pal/Ca2+-induced pore opens easier than in the low resistant animals, this being opposite for the classical, cyclosporin A-sensitive
MPT pore. The adaptation of the low resistant rats to oxygen deficiency increases the sensitivity of their mitochondria to
PalCaP inductors. The paper also discusses a possible role of the mitochondrial Pal/Ca2+-induced pore in the protection of tissues against hypoxia. 相似文献
16.
Mitochondrial permeability transition is typically characterized by Ca2+ and oxidative stress-induced opening of a nonselective proteinaceous membrane pore sensitive to cyclosporin A, known as the
permeability transition pore (PTP). Data from our laboratory provide evidence that the PTP is formed when inner membrane proteins
aggregate as a result of disulfide cross-linking caused by thiol oxidation. Here we compared the redox properties between
PTP in intact mitochondria and mitoplasts. The rat liver mitoplasts retained less than 5% and 10% of the original outer membrane
markers monoamine oxidase and VDAC, respectively. Kidney mitoplasts also showed a partial depletion of hexokinase. In line
with the redox nature of the PTP, mitoplasts that were more susceptible to PTP opening than intact mitochondria showed higher
rates of H2O2 generation and decreased matrix NADPH-dependent antioxidant activity. Mitoplast PTP was also sensitive to the permeability
transition inducer tert-butyl hydroperoxide and to the inhibitors cyclosporin A, EGTA, ADP, dithiothreitol and catalase. Taken together, these data
indicate that, in mitoplasts, PTP exhibits redox regulatory characteristics similar to those described for intact mitochondria. 相似文献
17.
Nogueira V Devin A Walter L Rigoulet M Leverve X Fontaine E 《Journal of bioenergetics and biomembranes》2005,37(1):25-33
The permeability transition pore (PTP) is a Ca2+-sensitive mitochondrial inner membrane channel involved in several models of cell death. Because the matrix concentration of PTP regulatory factors depends on matrix volume, we have investigated the role of the mitochondrial volume in PTP regulation. By incubating rat liver mitochondria in media of different osmolarity, we found that the Ca2+ threshold required for PTP opening dramatically increased when mitochondrial volume decreased relative to the standard condition. This shrinkage-induced PTP inhibition was not related to the observed changes in protonmotive force, or pyridine nucleotide redox state and persisted when mitochondria were depleted of adenine nucleotides. On the other hand, mitochondrial volume did not affect PTP regulation when mitochondria were depleted of Mg2+. By studying the effects of Mg2+, cyclosporin A (CsA) and ubiquinone 0 (Ub0) on PTP regulation, we found that mitochondrial shrinkage increased the efficacy of Mg2+ and Ub0 at PTP inhibition, whereas it decreased that of CsA. The ability of mitochondrial volume to alter the activity of several PTP regulators represents a hitherto unrecognized characteristic of the pore that might lead to a new approach for its pharmacological modulation. 相似文献
18.
A variety of stimuli utilize an increase of cytosolic free Ca2+ concentration as a second messenger to transmit signals, through Ca2+ release from the endoplasmic reticulum or opening of plasma membrane Ca2+ channels. Mitochondria contribute to the tight spatiotemporal control of this process by accumulating Ca2+, thus shaping the return of cytosolic Ca2+ to resting levels. The rise of mitochondrial matrix free Ca2+ concentration stimulates oxidative metabolism; yet, in the presence of a variety of sensitizing factors of pathophysiological relevance, the matrix Ca2+ increase can also lead to opening of the permeability transition pore (PTP), a high conductance inner membrane channel. While transient openings may serve the purpose of providing a fast Ca2+ release mechanism, persistent PTP opening is followed by deregulated release of matrix Ca2+, termination of oxidative phosphorylation, matrix swelling with inner membrane unfolding and eventually outer membrane rupture with release of apoptogenic proteins and cell death. Thus, a rise in mitochondrial Ca2+ can convey both apoptotic and necrotic death signals by inducing opening of the PTP. Understanding the signalling networks that govern changes in mitochondrial free Ca2+ concentration, their interplay with Ca2+ signalling in other subcellular compartments, and regulation of PTP has important implications in the fine comprehension of the main biological routines of the cell and in disease pathogenesis. 相似文献
19.
Michela Carraro Valentina Giorgio Justina ?ileikyt? Geppo Sartori Michael Forte Giovanna Lippe Mario Zoratti Ildikò Szabò Paolo Bernardi 《The Journal of biological chemistry》2014,289(23):15980-15985
Purified F-ATP synthase dimers of yeast mitochondria display Ca2+-dependent channel activity with properties resembling those of the permeability transition pore (PTP) of mammals. After treatment with the Ca2+ ionophore ETH129, which allows electrophoretic Ca2+ uptake, isolated yeast mitochondria undergo inner membrane permeabilization due to PTP opening. Yeast mutant strains ΔTIM11 and ΔATP20 (lacking the e and g F-ATP synthase subunits, respectively, which are necessary for dimer formation) display a striking resistance to PTP opening. These results show that the yeast PTP originates from F-ATP synthase and indicate that dimerization is required for pore formation in situ. 相似文献
20.
Mitochondria in Ca2+ Signaling and Apoptosis 总被引:8,自引:0,他引:8
Soraya S. Smaili Yi-Te Hsu Richard J. Youle James T. Russell 《Journal of bioenergetics and biomembranes》2000,32(1):35-46
Cellular Ca2+ signals are crucial in the control of most physiological processes, cell injuryand programmed cell death; mitochondria play a pivotal role in the regulation of such cytosolicCa2+ ([Ca2+]c) signals. Mitochondria are endowed with multiple Ca2+ transport mechanismsby which they take up and release Ca2+ across their inner membrane. These transport processesfunction to regulate local and global [Ca2+]c, thereby regulating a number of Ca2+-sensitivecellular mechanisms. The permeability transition pore (PTP) forms the major Ca2+ effluxpathway from mitochondria. In addition, Ca2+ efflux from the mitochondrial matrix occursby the reversal of the uniporter and through the inner membrane Na+/Ca2+ exchanger. Duringcellular Ca2+ overload, mitochondria take up [Ca2+]c, which, in turn, induces opening of PTP,disruption of mitochondrial membrane potential (m) and cell death. In apoptosis signaling,collapse of ;m and cytochrome c release from mitochondria occur followed by activationof caspases, DNA fragmentation, and cell death. Translocation of Bax, an apoptotic signalingprotein from the cytosol to the mitochondrial membrane, is another step during thisapoptosis-signaling pathway. The role of permeability transition in the context of cell death in relationto Bcl-2 family of proteins is discussed. 相似文献