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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…?

 


    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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