Tricarboxylic acid cycle, brain

Yudkoff, M., Nelson, D., Daikhin, Y. etal. Tricarboxylic acid cycle in rat brain synaptosomes. Fluxes and interactions with aspartate aminotransferase and malate/aspar-tate shuttle. /. Biol. Chem. 269 27414-27420,1994. 

The tricarboxylic acid cycle was therefore validated, having been tested not only in pigeon-breast muscle but also with brain, testis, liver, and kidney. The nature of the carbohydrate fragment entering the cycle was still uncertain. The possibility that pyruvate and oxaloacetate condensed to give a 7C derivative which would be decarboxy-lated to citrate, was dismissed partly because the postulated compound was oxidized at a very low rate. Further, work on the oxidation of fatty acids (see Chapter 7) had already established that a 2C fragment like acetate was produced by fatty acid oxidation, en route for carbon dioxide and water. It therefore seemed likely that a similar 2C compound might arise by decarboxylation of pyruvate, and thus condense with oxaloacetate. For some considerable time articles and textbooks referred to this unknown 2C compound as active acetate. ... 

During periods of hunger, muscle proteins serve as an energy reserve for the body. They are broken down into amino acids, which are transported to the liver. In the liver, the carbon skeletons of the amino acids are converted into intermediates in the tricarboxylic acid cycle or into acetoacetyl-CoA (see p. 175). These amphibolic metabolites are then available to the energy metabolism and for gluconeogenesis. After prolonged starvation, the brain switches to using ketone bodies in order to save muscle protein (see p. 356). 

In this section we have seen that fatty acids are oxidized in units of two carbon atoms. The immediate end products of this oxidation are FADH2 and NADH, which supply energy through the respiratory chain, and acetyl-CoA, which has multiple possible uses in addition to the generation of energy via the tricarboxylic acid cycle and respiratory chain. Unsaturated fatty acids can also be oxidized in the mitochondria with the help of auxiliary enzymes. Ketone body synthesis from acetyl-CoA is an important liver function for transfer of energy to other tissues, especially brain, when glucose levels are decreased as in diabetes or starvation. 

Hassel B, Sonnewald U (1995) Selective inhibition of the tricarboxylic acid cycle of GABAergic neurons with 3-nitropropionic add in vivo. J Neurochem 65 1184-1191 Henry PG, Lebon V, Vaufrey F, BrouiUet E, Hantraye P, Bloch G (2002) Decreased TCA cycle rate in the rat brain after acute 3-NPA treatment measured by in vivo 1H-[13C] NMR spectroscopy. J Neurochem 82 857-866... 

Bartnik, B.L., Sutton, R.L., Fukushima, M., Harris, N.G., Hovda, D.A., Lee, S.M. (2005). Upregulation of pentose phosphate pathway and preservation of tricarboxylic acid cycle flux after experimental brain injury. J. Neurotrauma 22 1052-65. 

Saito, T. (1990). Glucose-supported oxidative metabolism and evoked potentials are sensitive to fluoroacetate, an inhibitor of glial tricarboxylic acid cycle in the olfactory cortex slice. Brain Res. 535 205-13. 

The mechanism of MCA toxicity seems to be via inhibition of the enzyme pyruvate dehydrogenase this inhibition blocks the Krebs (tricarboxylic acid) cycle and disrupts the cell s energy supply. Almost immediately, the cell finds itself without energy. Ketoglutarate dehydrogenase activity is also reduced, which causes lactic acidosis. The MCA also damages the blood-brain barrier, probably through the formation of vascular endothelial microlesions. 

Van den Berg CJ, Mela P, Waelsch H (1966) On the contribution of the tricarboxylic acid cycle to the synthesis of glutamate, glutamine and aspartate in brain. Biochem Biophys Res Commun 23 479-484. 

Balazs, R., Machiyama, Y., Hammond, B. J., Julian, T. and Richter, D. (1970) The operation of the y-aminobutyrate bypath of the tricarboxylic acid cycle in brain tissue in vitro. Biochem. J., 116, 445-460. 

Gibson, G. E., et al., 2003. Deficits in a tricarboxylic acid cycle enzyme in brains from patients with Parkinson s disease. Neurochem Int. 43, 129-135. 

Cheng S.-C (1972) Compartmentation of Tricarboxylic Acid Cycle Intermediates and Related Metabolites, in Metabolic Compartmentation m the Brain (Balazs R and Cremer J E, eds ), pp 107-118 MacMillan, London... 

Though less than 1% of the total iron in the body is utilized for enzymes and cofactors, the critical nature of these enzymes in such major metabolic pathways as the tricarboxylic acid cycle could easily explain brain effects of iron deficiency. Pollitt and Leibel (1976) also suggest that central catecholamine excess causes some of the behavioral disturbances attributed to iron deficiency. Monoamine oxidase is functionally deranged in iron-deficient rats. Children with iron-deficient anemia have elevated urinary norepinephrine excretion which is normalized within 1 wk after parenteral iron treatment. Potentially toxic excess heme precursors, protoporphyrins, may also mediate the behavioral effects of iron deficiency. 

Acetyl-CoA. A key energy metabolite in the brain and all tissues serving as a source of dicarboxylic units feeding the tricarboxylic acid cycle. 

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