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Mitochondrial damage by Ca2+ Print E-mail

Damage to mitochondria by over-accumulated Ca2+.

? …is there any harm in mitochondrial permeability transition…?

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    Aside of mPTP opening (which may or may not be happening in living tissue), there are other well documented malfunctions caused to mitochondrial machinery by over-accumulated and retained Ca2+ (a situation which may or …see above):


  •    Inhibition of mitochondrial enzymes, respiration and oxidative phosphorylation by high Ca2+ is well documented [1-4]; among them are several “major” dehydrogenases of tricarboxylic acid cycle, including pyruvate dehydrogenase [4] and α-ketoglutarate dehydrogenase complex [3].

  •    Accumulated Ca2+ may also decrease the intramitochondrial pool of ADP, thus reducing the exchangeable pool and the amount of ADP available to the F1-ATPase [2].

  •    Accumulation of ~ 40 nmol Ca2+ by mitochondria strongly inhibits their ATP/ADP translocase (ANT) activity [5].

  •    Progressive accumulation of large amounts of Ca2+ and Pi results in Ca2+-Pi precipitate formation in the mitochondrial matrix [6, 7]. Mitochondria from neural tissues can accumulate such significant amounts of Ca2+ (2000-4000 nmol/mg protein, [7,8]), that the precipitate may literally fill up the mitochondrial matrix water space, thus creating diffusion limitations for substrate delivery to primary dehydrogenases.

To be continued someday.

REFERENCES:
[1]. Villalobo, A. and Lehninger, A.L., (1980) Inhibition of oxidative phosphorylation in ascites tumor mitochondria and cells by intramitochondrial Ca2+. Journal of Biological Chemistry, 255(6): p. 2457-64.
[2]. Roman, I., Clark, A., and Swanson, P.D., (1981) The interaction of calcium transport and ADP phosphorylation in brain mitochondria. Membrane Biochemistry, 4(1): p. 1-9.
[3]. Lai, J.C. and Cooper, A.J., (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. Journal of Neurochemistry, 47(5): p. 1376-86.
[4]. Lai, J.C., DiLorenzo, J.C., and Sheu, K.F., (1988) Pyruvate dehydrogenase complex is inhibited in calcium-loaded cerebrocortical mitochondria. Neurochemical Research, 13(11): p. 1043-8.
[5]. Gómez-Puyou A, Tuena de Gómez-Puyou M, Klapp M, Carafoli E (1979). The effect of calcium on the translocation of adenine nucleotides in rat liver mitochondria. Arch Biochem Biophys. 194(2):399-404. PMID: 443811
[6]. Kristian, T., Weatherby, T.M., Bates, T.E., and Fiskum, G., (2002) Heterogeneity of the calcium-induced permeability transition in isolated non-synaptic brain mitochondria. Journal of Neurochemistry, 83(6): p. 1297-308.
[7]. Chalmers, S. and Nicholls, D.G., (2003) The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. Journal of Biological Chemistry, 278(21): p. 19062-70.
[8]. Chinopoulos, C., Starkov, A.A., and Fiskum, G., (2003) Cyclosporin A-insensitive permeability transition in brain mitochondria: inhibition by 2-aminoethoxydiphenyl borate. Journal of Biological Chemistry, 278(30): p. 27382-9.

COPYRIGHT NOTICE: Whatever. You are free to use this information in whatsoever way pleases you, and without referring to this document. Composed by: STARKOV
Last Updated ( Friday, 08 January 2010 )
 

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