Permeability transition pores

Andrabi, S. A., Sayeed, I., Siemen, D., Wolf, G. Horn, T. F. (2004). Direct inhibition of the mitochondrial permeability transition pore a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J. 18, 869-71. 

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],... 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

Figure 11.6 Schematic representation of Ca2+ transport in and out of mitochondria, showing all the Ca2+ transporters and activation of matrix dehydrogenases. PTP—permeability transition pore. (From Carafoli, 2003. Copyright 2003, with permission from Elsevier.)...

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... 

Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria, Proc.Natl.Acad.Sci. U.S.A. 95 14681-14686. 

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. 

Mattiasson G, Friberg H, Hansson M, Elmer E, Wieloch T. 2003. Flow cytometric analysis of mitochondria from CAl and CA3 regions of rat hippocampus reveals differences in permeability transition pore activation. J Neurochem 87 532-544. 

Kroemer G. The mitochondrial permeability transition pore complex as a pharmacological target. An introduction. Curr Med Chem 2003 10(16) 1469-1472. 

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. 

Critical for predictivity in a recent comprehensive study was the number and choice of parameters measured [4]. Early, sublethal effects on cell proliferation, cell morphology and mitochondria occurred consistently and ubiquitously with toxicity and when used collectively were most diagnostic. It is noteworthy that the toxicity of many drugs is attributable to various mitochondrial targets, including oxidative phosphorylation, fatty acid oxidation, Krebs cycling, membrane transport, permeability transition pore, proliferation and oxidative stress (Table 14.4). 

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... 

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... 

Drugs that Induce the Mitochondrial Permeability Transition Pore (MPT)... 

Juhaszova, M. et al. (2008) The identity and regulation of the mitochondrial permeability transition pore where the known meets the unknown. Annals of the New York Academy of Sciences, 1123, 197-212. 

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. 

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... 

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