Alternative mitochondrial functions in cell physiopathology: beyond ATP production

It is well known that mitochondria are the main site for ATP generation within most tissues. However, mitochondria also participate in a surprising number of alternative activities, including intracellular Ca2+ regulation, thermogenesis and the control of apoptosis. In addition, mitochondria are the main cellular generators of reactive oxygen species, and may trigger necrotic cell death under conditions of oxidative stress. This review concentrates on these alternative mitochondrial functions, and their role in cell physiopathology.24125

Alternative mitochondrial functions in cell physiopathology: beyond ATP production

It is well known that mitochondria are the main site for ATP generation within most tissues. However, mitochondria also participate in a surprising number of alternative activities, including intracellular Ca2+ regulation, thermogenesis and the control of apoptosis. In addition, mitochondria are the main cellular generators of reactive oxygen species, and may trigger necrotic cell death under conditions of oxidative stress. This review concentrates on these alternative mitochondrial functions, and their role in cell physiopathology

Mitochondrial Permeability Transition And Oxidative Stress

Mitochondrial permeability transition (MPT) is a non-selective inner membrane permeabilization that may precede necrotic and apoptotic cell death. Although this process has a specific inhibitor, cyclosporin A, little is known about the nature of the proteinaceous pore that results in MPT. Here, we review data indicating that MPT is not a consequence of the opening of a pre-formed pore, but the consequence of oxidative damage to pre-existing membrane proteins. © 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.4951-21215Liu, X., Kim, C.N., Yang, J., Jemmerson, R., Wang, X., (1996) Cell, 86, pp. 147-157Susin, S.A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Kroemer, G., (1996) J. Exp. Med., 184, pp. 1331-1341Green, D.R., Reed, J.C., (1998) Science, 281, pp. 1309-1312Skulachev, V.P., (1998) FEBS Lett., 423, pp. 275-280Kroemer, G., (1999) Biochem. Soc. 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Ca2+-induced Mitochondrial Membrane Permeabilization: Role Of Coenzyme Q Redox State

Rotenone-poisoned rat liver mitochondria energized by succinate addition, after a 5-min period of preincubation in presence of 10 μM Ca2+, produce H2O2 at much faster rates, undergo extensive swelling, and are not able to retain the membrane potential and accumulated Ca2+. Similar results were obtained when a suspension of rat liver mitochondria preincubated in anaerobic medium for 5 min was reoxygenated. The addition of either ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid, ruthenium red, catalase, or dithiothreitol, just before succinate or O2 addition, prevented mitochondrial swelling, indicating the involvement of Ca2+, reactive oxygen species, and oxidation of membrane protein thiols in this process of membrane permeabilization. Inhibition of mitochondrial swelling by cyclosporin A suggests that the membrane alterations observed under these experimental conditions are related to opening of the permeability transition pore. The presence of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, which prevents Ca2+ cycling across the membrane, did not inhibit mitochondrial swelling when Ca2+ influx into the mitochondrial matrix was driven by a high Ca2+ gradient. When rotenone plus antimycin A-poisoned mitochondria were energized by N,N,N',N'-tetramethyl-p-phenylenediamine, which reduces respiratory chain complex IV, mitochondrial swelling did not occur, unless succinate, which reduces coenzyme Q, was also added. It is concluded that reduced coenzyme Q is the electron source for oxygen radical production during Ca2+-stimulated oxidative damage of mitochondria.2691 38-1C141C14

3,5,3'-triiodothyronine Induces Mitochondrial Permeability Transition Mediated By Reactive Oxygen Species And Membrane Protein Thiol Oxidation

Ca2+-loaded rat liver mitochondria treated with 3,5,3'- triiodothyronine (T3) undergo nonspecific inner membrane permeabilization, as evidenced by mitochondrial swelling, a decrease in membrane potential (ΔΨ), and an increase in the rate of oxygen uptake. T3 analogues thyroxine (T4), 3',5'-diiodothyronine (T2), and 3,5',3'-triiodothyronine (reverse T3), in decreasing order of potency, resulted in a similar but less extensive effect. Permeabilization induced by T3 is dependent on Ca2+ (1 μM) and T3 (0.5-25 μM) concentrations and is inhibited by cyclosporin A, a known inhibitor of mitochondrial permeability transition. Catalase or dithiothreitol also prevents membrane permeabilization, suggesting the participation of membrane protein thiol group oxidation induced by reactive oxygen species. The determination of the mitochondrial membrane protein thiol group content after treatment with Ca2+ and T3 shows a significant decrease, due to thiol oxidation. When mitochondria are incubated in the presence of inorganic phosphate and the protonophore carbonyl cyanide p- trifluoromethoxyphenylhydrazone, mitochondrial swelling still occurs after treatment with T3 and high Ca2+ concentrations, suggesting that mitochondrial permeabilization is not dependent on T3-induced ΔΨ or matrix pH alterations. Under these experimental conditions, when no oxygen is present in the incubation medium, no permeabilization occurs, suggesting that the permeabilization is dependent on mitochondrial-generated reactive oxygen species. Confirming this hypothesis, superoxide generation in a suspension of submitochondrial particles is increased when T3 is present. Our results lead to the conclusion that T3 induces a situation of oxidative stress in isolated liver mitochondria, with Ca2+-mediated membrane protein thiol oxidation and nonspecific inner membrane permeabilization.3541151157Soboll, S., (1993) Biochim. Biophys. 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The Thiol-specific Antioxidant Enzyme Prevents Mitochondrial Permeability Transition: Evidence For The Participation Of Reactive Oxygen Species In This Mechanism

Mitochondrial swelling and membrane protein thiol oxidation associated with mitochondrial permeability transition induced by Ca2+ and inorganic phosphate are inhibited in a dose-dependent manner either by catalase, the thiol-specific antioxidant enzyme (TSA), a protein recently demonstrated to present thiol peroxidase activity, or ebselen, a selenium-containing heterocycle which also possesses thiol peroxidase activity. This inhibition of mitochondrial permeability transition is due to the removal of mitochondrial-generated H2O2 which can easily diffuse to the extramitochondrial space. Whereas ebselen required the presence of reduced glutathione as a reductant to grant its protective effect, TSA was fully reduced by mitochondrial components. Decrease in the oxygen concentration of the reaction medium also inhibits mitochondrial permeabilization and membrane protein thiol oxidation, in a concentration-dependent manner. The results presented in this report confirm that mitochondrial permeability transition induced by Ca2+ and inorganic phosphate is reactive oxygen species- dependent. The possible importance of TSA as an intracellular antioxidant, avoiding the onset of mitochondrial permeability transition, is discussed in the text.273211276612769Gunter, T.E., Gunter, K.K., Sheu, S.-S., Gavin, C.E., (1994) Am. J. Physiol., 267, pp. C313-C339Zoratti, M., Szabó, I., (1995) Biochim. Blophys. Acta, 1241, pp. 139-176Lehninger, A.L., Vercesi, A.E., Bababunmi, E.A., (1978) Proc. Natl. Acad. Sci. U. S. A., 79, pp. 6842-6846Vercesi, A.E., Kowaltowski, A.J., Grijalba, M.T., Meinicke, A.R., Castilho, R.F., (1997) Biosci. Rep., 17, pp. 43-52Castilho, R.F., Kowaltowski, A.J., Meinicke, A.R., Vercesi, A.E., (1995) Free Radical Biol. & Med., 18, pp. 479-486Kowaltowski, A.J., Castilho, R.F., Vercesi, A.E., (1995) Am. J. Physiol., 269, pp. C141-C147Valle, V.G.R., Fagian, M.M., Parentoni, L.S., Meinicke, A.R., Vercesi, A.E., (1993) Arch. Biockem. Biophys., 307, pp. 1-7Kowaltowski, A.J., Castilho, R.F., Vercesi, A.E., (1996) FEBS Lett., 378, pp. 150-152Kowaltowski, A.J., Castilho, R.F., Grijalba, M.T., Bechara, E.J.H., Vercesi, A.E., (1996) J. Biol. Chem., 271, pp. 2929-2934Fagian, M.M., Pereira-da-Silva, L., Martins, I.S., Vercesi, A.E., (1990) J. Biol. Chem., 265, pp. 19955-19960Castilho, R.F., Kowaltowski, A.J., Vercesi, A.E., (1996) J. Bioenerg. Biomembr., 28, pp. 523-529Scorrano, L., Petronilli, V., Bernardi, P., (1997) J. Biol. Chem., 272, pp. 12295-12299Pastorino, J.G., Snyder, J.W., Serroni, A., Hoek, J.B., Farber, J.L., (1993) J. Biol. Chem., 268, pp. 13791-13798Griffiths, E., Halestrap, A.P., (1995) Biochem. J., 307, pp. 93-98Zamzami, N., Hirsch, T., Dallaporta, B., Petit, P.X., Kroemer, G., (1997) J. Bioenerg. Biomembr., 29, pp. 185-193Skulachev, V.P., (1996) FEBS Lett., 397, pp. 7-10Kim, K., Kim, I.H., Lee, K.-Y., Rhee, S.G., Stadtman, E.R., (1988) J. Biol. Chem., 263, pp. 4704-4711Chae, H.Z., Robison, K., Poole, L.B., Church, G., Storz, G., Rhee, S.G., (1994) Proc. Natl. Acad. Sci. U. S. A., 91, pp. 7017-7021Chae, H.Z., Chung, S.J., Rhee, S.G., (1994) J. Biol. Chem., 269, pp. 27670-27678Netto, L.E.S., Chae, H.Z., Kang, S.-W., Rhee, S.G., Stadtman, E.R., (1996) J. Biol. Chem., 271, pp. 15315-15321Nogoceke, E., Gommel, D.U., Kieb, M., Kalisz, H.M., Flohé, L., (1997) Biol. Chem., 378, pp. 827-836Kim, I.H., Kim, K., Rhee, S.G., (1989) Proc. Natl. Acad. Sci. U. S. A., 86, pp. 6018-6022Watabe, S., Kohno, H., Kouyama, H., Hiroi, T., Yago, N., Nakazawa, T., (1994) J. Biochem. (Tokyo), 115, pp. 648-654Ishii, T., Kawane, T., Taketani, S., Bannai, S., (1995) Biochem. Biophys. Res. Commun., 216, pp. 970-975Sies, H., (1993) Free Radical Biol. & Med., 14, pp. 313-323Kowaltowski, A.J., Vercesi, A.E., Castilho, R.F., (1997) Biochim. Biophys. Acta, 1318, pp. 385-402Boveris, A., Martino, E., Stoppani, A.O.M., (1977) Anal. Biochem., 80, pp. 145-158Chae, H.Z., Uhm, T.B., Rhee, S.G., (1994) Proc. Natl. Acad. Sci. U. S. A., 91, pp. 7022-7026Tsuji, K., Copeland, N.G., Jenkins, N.A., Obinata, M., (1995) Biochem. J., 307, pp. 377-381Zhang, P., Liu, B., Kang, S.W., Seo, M.S., Rhee, S.G., Obeid, L.M., (1997) J. Biol. Chem., 272, pp. 30615-3061

Mitochondrial Energy Metabolism And Redox State In Dyslipidemias

Changes in mitochondrial function are intimately associated with metabolic diseases. Here, we review recent evidence relating alterations in mitochondrial energy metabolism, ion transport and redox state in hypercholesterolemia and hypertriglyceridemia. We focus mainly on changes in mitochondrial respiration, K+ and Ca2+ transport, reactive oxygen species generation and susceptibility to mitochondrial permeability transition. © 2007 IUBMB.5904/05/15263268Newmeyer, D.D., Ferguson-Miller, S., Mitochondria: Releasing power for life and unleashing the machineries of death (2003) Cell, 112, pp. 481-490Green, D.R., Kroemer, G., The pathophysiology of mitochondrial cell death (2004) Science, 305, pp. 626-629Orrenius, S., Gogvadze, V., Zhivotovsky, B., Mitochondrial oxidative stress: Implications for cell death (2006) Annu. Rev. Pharmacol. 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Oxidative Damage Of Mitochondria Induced By Fe(ii)citrate Or T-butyl Hydroperoxide In The Presence Of Ca2+: Effect Of Coenzyme Q Redox State

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