Permeability Transition Pore Opening

Dying cells usually show characteristics of both apoptotic and necrotic cell death. This is because the Bax/Bak and PTP opening pathways have cross-talk at several 

Stress Is Sensed by BH3-only Proteins. — BH3-only proteins inhibit anti-apoptotic Bcl-2 proteins. Bax/Bak pore is formed. — Cytochrome c and other apoptotic proteins are released from mitochondria. - They activate caspases. - Caspases cleave the complex I subunit of the respiratory chain. - It causes loss of membrane potential and generates ROS. - ROS modulates and open PTP and activates BH3-only proteins. 

PTP Is Modulated by ROS or by Ca2+. - It releases cytochrome c and other apoptotic proteins and causes loss of membrane potential. - More ROS is generated and caspases are activated. — ROS activates BH3-only proteins. -  

Respiratory Chain Is Blocked or Damaged by Toxicants. — Membrane potential is declined and ROS is generated. ROS causes PTP opening and activates BH3-only proteins. - Apoptotic proteins are released frommitochondria. - Cytochrome c activates caspases. 

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Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Permeability transition pore Opening by reactive oxygen species, reactive nitrogen species, bile adds, ihio crosslinkers, atractyloside, betu-liniate, lonidamidem various anticancer drugs, to collapse mitochondrial membrane potential and activate mitochondrial apoptotic pathway... 

Halestrap AP, Clarke SJ, Javadov SA (2004) Mitochondrial permeability transition pore opening during myocardial reperfusion - a target for cardioprotection. Cardiovasc Res 61(3) 372—385 Harrison GJ, Cemiway RJ, Peart J, Berr SS, Ashton K, Regan S, Matheme GP, Headrick JP (2002) Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc Res 53(1) 147-155... 

Hausenloy D, Wynne A, Duchen M, Yellon D (2004) Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 109(14) 1714—1717... 

Halestrap, A.P., Clarke, S.J., and Javadov, S.A. 2004. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc. Res. 61 372-385. 

Figure 17.7. Two types of mitochondrial membrane permeabilization. Upper Bax/Bak pore leads to release of intermembrane space proteins, but the inner membrane is intact. Lower PTP (permeability transition pore) opening destroys the impermeability of the inner mitochondrial membrane (IMM). The pore opening causes influx of solutes and water into the matrix resulting in swelling. The mitochondrial swelling ruptures outer mitochondrial membrane (OMM). CypD, cyclophilin D.

D. J. Hausenloy, H. L. Maddock, G. F. Baxter and D. M. Yellon, Inhibiting mitochondrial permeability transition pore opening a new paradigm for myocardial preconditioning Cardiovasc Res 55,534-543, (2002). 

Increase in mitochondrial membrane permeability permeability transition pore opening (PT) decrease in mitochondrial membrane potential (MMP) JC-1 and JC-9 carbocyanine dyes Mito Tracker and MitoFluor dyes TMRME and Rhodamine 123 Flourescent probe, calcein redistribution Radiolabeled deoxyglucose Large changes may not be specifi for apoptosis subtle changes, more characteristic of apoptosis may not be measurable alterations may be reversible... 

Accumulated evidence from recent research indicates that mitochondria-derived factors, such as cytochrome c, have an important role in the apoptosis of some cells. Previous reports show that cytochrome c and caspase-9 participate in Apafl apoptosome, a complex important for caspase-3 activation. Cytochrome c was released from mitochondria of HL-60 cells during treatment with carnosic acid, carnosol or ursolic acid. Previous evidence showed that mitochondria permeability transition (MPT) coupled with depolarization of the membrane potential induces the release of cytochrome c (31-33). It also has been reported that cytochrome c released from mitochondria can precede dissipation of the voltage gradient (the mitochondrial transmembrane potential vi/ ) across the membrane, suggesting that the escape of cytochrome c from mitochondria occurs prior to permeability transition pore opening (loss of mitochondrial transmembrane potential) (34,35). Here we observed the depolarization of the mitochondrial membrane potential in HL-60 cells by treatment with carnosic acid, carnosol, or ursolic acid for Ih. Cytochrome c was released after 3h treatment of carnosic acid, carnosol, or ursolic acid. 

A dissipation of mitochondrial membrane potential (A P/w) is often detectable dining apoptosis (Green, 1998 Shidoji et al, 1997). A loss of A Pm is thonght to be mediated by the opening of the mitochondrial permeability transition pore which is proposed to be involved in mitochondrial efflux of cytochrome c into the cytosol (Scarlett and Mnrphy, 1997). However, a recent report by Bossy-Wetzel et al (1998) provided... 

Scorrano, L., PetroniUi, V., Di Lisa, F., and Bemardi, P., 1999, Commitment to apoptosis by GD3 ganglioside depends on opening ofthe mitochondrial permeability transition pore. J Biol Chem 274 22581-22585. 

Kidd JF, Pilkington MF, Schell MJ, et al. Paclitaxel affects cytosolic calcium signals by opening the mitochondrial permeability transition pore. J Biol Chem 2002 277(8) 6504-6510. 

Much progress has been made in understanding the different mechanisms that can cause mitochondrial dysfunction, such as (i) uncoupling of electron transport from ATP synthesis by undermining integrity of inner membrane (ii) direct inhibition of electron transport system components (iii) opening of the mitochondrial permeability transition pore leading to irreversible collapse of the transmembrane potential and release of pro-apoptotic factors (iv) inhibition of the... 

The structure of doxorubicin includes a quinone moiety therefore, it can easily accept an electron and undergo redox cycling (Fig. 7.47). Because it accumulates in the mitochondria, it can accept electrons from the electron transport chain and divert them away from complex I. It becomes reduced to the semiquinone radical in the process. This will then reduce oxygen to superoxide and return to the quinone form (Fig. 7.47). This could lead to oxidation of GSH and mtDNA. The subsequent damage may lead to the opening of the mitochondrial permeability transition pore. Consequently, mitochondrial ATP production will be compromised, and ATP levels will decline. 

Bernardi, P., 1992, Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by the proton electrochemical gradient. Evidence that the pore can be opened by membrane depolarization, J. Biol. Chem. 267, pp. 8834-8839... 

Di Lisa, F., Menabo, R., Canton, M., Barile, M., and Bernardi, P., 2001, Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart, J. Biol. Chem. 276, pp. 2571-2575... 

Feldmann, G., Haouzi, D., Moreau, A., Durand, S. A., Bringuier, A., Berson, A., Mansouri, A., Fau, D., and Pessayre, D., 2000, Opening of the mitochondrial permeability transition pore causes matrix expansion and outer membrane rupture in Fas-mediated hepatic apoptosis in mice, Hepatology 31, pp. 674-683... 

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