Abstract
Alanine is a nutritionally nonessential amino acid synthesized by transamination of pyruvate originated from glucose. Alanine is the principal gluconeogenic amino acid because it can originate pyruvate and glucose through the inverse pathway. Considering that it has been suggested that alanine could be used as a dietary supplement in combination with growth hormone in the treatment of undernourished children affected by some inherited metabolic diseases to induce anabolism, the principal objective of the present work was to measure the activities of the mitochondrial respiratory chain complexes and succinate dehydrogenase in brain cortex of Wistar rats subjected to chronic alanine administration from the 6th to the 21st day of life. We also investigated the in vitro effect of alanine on the activities of mitochondrial respiratory chain complexes and succinate dehydrogenase in the same brain structure of 22-day-old rats. The results showed a reduction of Complex I + III and succinate dehydrogenase activities in brain cortex of rats subjected to alanine administration. We also verified that alanine inhibited the in vitro activity of Complexes I + III by competition with NADH. These results indicate that more investigation would be necessary before considering alanine supplementation as a valid adjuvant therapy to sick children with these disorders.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
Babcock, G.T., and Wikström, M. (1992). Oxygen activation and the conservation of energy in cell respiration. Nature 356:301-309.
Balász, R. (1965). Control of glutamate metabolism. The effect of pyruvate. J. Neurochem. 12:63-67.
Bãnos, G., Daniel, P.M., and Pratt, O.E. (1978). The effect of age upon the entry of some amino acids into de brain and its incorporation into cerebral protein. Dev. Med. Child Neurol. 20:335-346.
Beal, M.F. (2000). Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci. 23:298-304.
Beyer, R. (1991). An analysis of the role of coenzyme Q in free radical generation and as an anti-oxidant. Biochem. Cell Biol. 70:343-390.
Bonomi, F., Pagani, S., and Cerletti, P. (1982). Recent advances on the mechanism of the active-non-active transition of succinate dehydrogenase. J. Mol. Catal. 14:185-196.
Chinopoulos, C., and Adam-Vizi, V. (2001). Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: Relevance to Parkinson's disease. J. Neurochem. 76:302-306.
Di Donato, S. (2000). Disorders related to mitochondrial membranes: Pathology of the respiratory chain and neurodegeneration. J. Inherit. Metab. Dis. 23:247-263.
Di Lisa, F., and Bernardi, P. (1998). Mitochondrial function a determinant of recovery or death in cell response to injury. Mol. Cell. Biochem. 184:379-391.
Erecinska, M., Nelson, D., Nissim, I., Daikhin, Y., and Yudkoff, M. (1994). Cerebral alanine transport and alanine aminotransferase reaction: Alanine as a source of glutamate. J. Neurochem. 62:1953-1964.
Fischer, J.C., Ruitenbeek, W., Berden, J.Á., Trijbels, J.M., Veerkamp, J.H., Stadhouders, A.M., Sengers, R.C., and Janssen, A.J. (1985). Differencial investigation of the capacity of succinate oxidation in human skeletal muscle. Clin. Chim. Acta 153:23-36.
Gutman, M. (1976). The effect of opposing effectors on activation level of succinate dehydrogenase: Equilibrium and kinetic studies. Biochemistry 15:1342-1348.
Hasegawa, E., Takeshige, K., Oishi, T., Murai,Y., and Minikami, S. (1990). 1-Methyl-4-phenylpyridinium (MPPC) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles. Biochem. Biophys. Res. Commun. 170:1049-1055.
Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265-275.
Marsden, D., Barshop, B.A., Capistrano-Estrada, S., Rice, M., Prodanus, C., Sartoris, D., Wolff, J., Jones, K.L., Spector, S., and Nyhan,W.L. (1994). Anabolic effect of human hormone: Management of inherited disorders of catabolic pathways. Biochem. Med. Metab. Biol. 52:145-154.
Massieu, L., Del Rio, P., and Montiel, T. (2001). Neurotoxicity of glutamate uptake inhibition in vivo: Correlation with succinate dehydrogenase activity and prevention by energy substrates. Neuroscience 106:669-677.
Pitkãnen, S., and Robinson, B.H. (1996). Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J. Clin. Invest. 98:345-351.
Ramsey, R.R., Krueger, M.J., Youngster, S.K., Gluck, M.R., Casida, J.E., and Singer, J. (1991). Interaction of 1-methyl-4-phenylpiridinium ion (MPPC) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase. J. Neurochem. 56:1184-1190.
Robinson, B.H. (1994). Human complex I deficiency: Clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect. Biochim. Biophys. Acta 1364:271-276.
Rodwell, V.W. (2000). Biosynthesis of the nutritionally nonessential amino acids. In (R.K. Murray, D.K. Granner, P.A, Mayes, and V.W. Rodwell, eds.), Harpers Biochemistry, 25th edn., Appleton & Lange, Stamford.
Rustin, P., Chretien, D., Bourgeron, T., Gírard, B., Rötig, A., Saudubray, J.M., and Munnich, A. (1994). Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chim. Acta 228:35-51.
Rutter, G.A., and Rizzuto, R. (2000). Regulation of mitochondrial metabolism by ERCa2C release: An intimate connection. Trends Biochem. Sci. 25:215-221.
Schapira, A.H. (1999). Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia an Friedreich's ataxia. Biochim. Biophys. Acta 1410:159-170.
Schapira, A.H., Cooper, J.M., Dexter, D., Clark, J.B., Jenner, P., and Marsden, C.D. (1990). Mitochondrial complex I deficiency in Parkinson's disease. J. Neurochem. 54:823-827.
Schinder, A.F., Olson, E.C., Spitzer, N.C., and Montal, M. (1996). Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J. Neurosci. 16:6125-6133.
Sorensen, R.G., and Mahler, H.R. (1982). Localization of endogenous ATPases at the nerve terminal. J. Bioenerg. Biomembr. 14:527-547.
Takeshiga, K., and Minakami, S. (1979). NADH and NADPH-dependent formation of superoxide anions by bovine heart submitochondrial particles and NADH-ubiquinone reductase preparation. Biochem. J. 180:129-135.
Tanji, K., and Bonilla, E. (2000). Neuropathological aspects of cytochrome c oxidase deficiency. Brain Pathol. 10:420-430.
Wallace, D.C. (1999). Mitochondrial diseases in man and mouse. Science 283:1482-1488.
Wyse, A.T.S., Noriler, M.E., Borges, L.F., Floriano, P.J., Silva, C.G., Wajner, M., and Wannmacher, C.M.D. (1999). Alanine prevents the decrease of Na+,K+-ATPase activity in experimental phenylketonuria. Metab. Brain Dis. 14:95-101.
Rights and permissions
About this article
Cite this article
Rech, V.C., Feksa, L.R., Dutra-Filho, C.S. et al. Inhibition of the Mitochondrial Respiratory Chain by Alanine in Rat Cerebral Cortex. Metab Brain Dis 17, 123–130 (2002). https://doi.org/10.1023/A:1019973719399
Issue Date:
DOI: https://doi.org/10.1023/A:1019973719399