Mitochondrial Permeability

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. 

During the process of cell death, cytochrome c is released from mitochondria into the cytosol where it assists to activate the caspases, a family of killer caspases that trigger cell death, hi this chapter evidence that transmission of cell death signals into the release of cytochrome c involves phospholipids at several stages will be presented. Thus, phospholipids target proapoptotic proteins to mitochondria, enable these or other proteins to form channels or pores and to break the mitochondrial permeability barrier. Finally, peroxidation or increased levels of disrupt the ability of cardiolipin to interact with cytochrome c, initiating a sequence of events that ultimately lead to cell death. 

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... 

Kristal, B. S., and Brown, A. M., 1999b, Ganghoside GD3, the mitochondrial permeability transihon, and apoptosis. ArmN YAcad Sci 893 321-324. 

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. 

The main differences between necrosis and apoptosis are in the triggers (accidental v. physiological), the process (energy-independent vs. dependent), and the outcomes (with vs. without inflammation). However, apoptosis and/or necrosis can be induced by the same causes in some cases (K16). Alteration of mitochondrial permeability is involved in both apoptosis and necrosis (K16). Both apoptosis and necrosis are found in conditions such as stroke and myocardial infraction (F5), and necrosis can occur secondary to apoptosis (T4). To preserve the usefulness of the two terms for denoting different modes of cell death while still recognizing possible overlap of the two processes (H7), some more descriptive terms have been proposed primary necrosis (oncosis, ischemic cell death) (Ml) and secondary necrosis (apoptotic necrosis, necrosis secondary to apoptosis) (K15). 

During apoptosis, the mitochondrial permeability is altered and apoptosis-specific protease activators are released from this organelle. The discontinuity of the outer mitochondrial membrane results in the release of cytochrome C to the cytosol followed by subsequent depolarization of the inner mitochondrial membrane (C5, PI). The release of cytochrome C further promotes activation of cas-pases, which are important molecules for initiating apoptosis (T6). Apoptosis inducing factor (AIF), another molecule released into the cytoplasm, has proteolytic activity and is by itself sufficient to induce apoptosis. 

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... 

Cinnamaldehyde Cinnamomum cassia) is a potent inducer of apoptosis via ROS generation, thereby inducing mitochondrial permeability, depletion of intracellular thiols, activation of caspase-3 and DNA fragmentation [364]. Farnesol was also found to initiate apoptotic cell death [312, 318, 365], while other studies showed that dietary administration of cinnamaldehyde significantly inhibited pulmonary tumorigenesis in mice [366]. 

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