Mitochondrial permeability transition

Mitochondrial permeability transition involves the opening of a larger channel in the inner mitochondrial membrane leading to free radical generation, release of calcium into the cytosol and caspase activation. These alterations in mitochondrial permeability lead eventually to disruption of the respiratory chain and dqDletion of ATP. This in turn leads to release of soluble intramito-chondrial membrane proteins such as cytochrome C and apoptosis-inducing factor, which results in apoptosis. 

Hinson, J.A. Reid, A.B. McCullough, S.S. James, L.P. (2004). Acetaminophen-induced hepatotoxicity role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metabolism Reviews, Vol.36, No. 3-4, (January 2004), pp. 805-822, ISSN 0360-2532. 

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. 

Bradham, C.A., Qian, T., Streetz, K., Trautwein, C., Brenner, D.A., and Lemasters, J.J., 1998, The mitochondrial permeability transition is required for Tumor Necrosis Factor Alpha-mediated apoptosis and cytochrome c release, Molecular and Cellular Biology 18 6353-6364. 

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. 

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. 

Custodio JB, Cardoso CM, Madeira VM, Almeida LM. Mitochondrial permeability transition induced by the anticancer drug etoposide. Toxicol In Vitro 2001 15(4-5) 265-270. 

B. Yerushalmi, R. Dahl, M. W. Devereaux, E. Gumpricht and R. J. Sokol, Bile-acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology, 2001, 33(3), 616. 

Degeneration Mitochondrial permeability transition with membrane depolarization, cytochrome c release, and mitochondrial swelling and fragmentation activation of caspases and cell death pathway, endonuclease fragmentation of DNA with chromatin and nuclear condensation phosphatidyserine exposure on cell surface cytoskeletal disruption with membrane blebbing... 

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. 

H7. Hirsch, T., Marchetti, R, Susin, S. A., Dallaporta, B., Zamzami, N., Marzo, L, Geuskens, M., and Kroemer, G., The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death. Oncogene 15, 1573-1581 (1997). 

Since flavonoids are able to bind to the BDZ binding site of the GABA-A receptor, they might well interact with the BDZ binding site of the mitochondrial permeability transition protein, thereby modulating oxidative stress-induced apoptosis. ... 

Haonzi D, Lekahal M, Moreau A et al (2000) Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, cuspate activation and apoptosis in rat hepatocytes. Hepatology 32 303-311... 

However, two events occur as a result, which diminish initially the pathological consequences. These are that the phosphate combines with Ca2+ to form insoluble salt, so limiting any rise in cytosolic free Ca2+, and the drop in pH limits the activity of hydrolytic enzymes such as phospholipase and the mitochondrial permeability transition. These events will be discussed later in this chapter. 

Explain the mitochondrial permeability transition and why it is important in cell toxicity. 

Lemasters JJ, Nieminen A-L, Qian T, et al. The mitochondrial permeability transition in cell death a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1998 1366 177-196. 

Qian T, Herman B, Lemasters JJ. The mitochondrial permeability transition mediates both necrotic and apoptotic death of hepatocytes exposed to Br-A23187. Toxicol AppI Pharmacol 1999 154 117-125. 

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. 

MTP mitochondrial permeability transition, mucosa mucus membrane. 

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