Pyruvate dehydrogenase complex is inhibited in calcium-loaded cerebrocortical mitochondria
- 53 Downloads
An impairment of mitochondrial functions as a result of Ca-loading may be one of the significant events that lead to neuronal death after an ischemic insult. To assess the metabolic consequences of excess Ca on brain mitochondria, pyruvate oxidation was studied in isolated cerebrocortical mitochondria loaded with Ca in vitro. The flux of pyruvate dehydrogenase complex (PDHC) ([1-14C]pyruvate decarboxylation) was inhibited as the mitochondria accumulated excess Ca under the conditions tested: the inhibition in state 3 (i.e., in the presence of added ADP) was greater than in state 4 (i.e., in the absence of added adenine nucleotides). In state 4, the inhibition of the PDHC flux was accompanied by a similar reduction of the in situ activity of PDHC, indicating a change in PDHC phosphorylation. In state 3, the inhibition of the PDHC flux was greater than the corresponding decrease of the in situ PDHC activity. Thus, mechanisms other than the phosphorylation of PDHC might also contribute to the inhibition of pyruvate oxidation. Measurement of PDHC enzymatic activity in vitro indicated that PDHC, similar to α-ketoglutarate dehydrogenase complex, was inhibited by millimolar levels of Ca. This observation suggests that PDHC may also be inhibited non-covalently in Ca-loaded mitochondria in a manner similar to that of α-ketoglutarate dehydrogenase complex.
Key WordsBrain Mitochondria calcium ischemia protein phosphorylation pyruvate dehydrogenase
Unable to display preview. Download preview PDF.
- 1.Siesjö, B. K. 1981. Cell damage in the brain: A speculative synthesis. J. Cerb. Blood Flow Metab. 1:155–185.Google Scholar
- 4.Cheung, J. Y., Bonventre, J. V., Malis, C. D., and Leaf, A. 1986. Calcium and ischemic injury. N. Eng. J. Med. 314:1670–1676.Google Scholar
- 11.Åkerman, K. O., and Nicholls, D. G. 1983. Physiological and bioenergetic aspects of mitochondrial calcium transport. Rev. Physiol. Biochem Pharmacol. 35:149–201.Google Scholar
- 12.Carafoli, E. 1987. Intracellular calcium homeostasis. Ann. Rev. Biochem. 56:395–433.Google Scholar
- 19.Wieloch, T., and Koide, T. 1987. Pyruvate dehydrogenase is inhibited in the recirculation period following transient cerebral ischemia. J. Cereb. Blood Flow Metab. 7 (Suppl. 1): S75.Google Scholar
- 20.Welsh, F. A., Katayama, Y., and McKee, A. E. 1988. Effect of dichloroacetate on metabolite recovery following ischemia. Trans. Am. Soc. Neurochem. 19:149.Google Scholar
- 21.Randle, P. J. 1981. Phosphorylation-dephosphorylation cycles and the regulation of fuel selection in mammals. Pages 107–129,in Eastabrook, R. W., and Srere, P. (eds.), Current Topics of Cellular Regulations, Vol. 18, Academic Press, New York.Google Scholar
- 22.Wieland, O. H. 1983. The mammalian pyruvate dehydrogenase complex: Structures and regulation. Rev. Physiol. Biochem. Pharmacol. 96:127–170.Google Scholar
- 27.Sheu, K.-F. R., Lai, J. C. K., DiLorenzo, J. C., and Blass, J. P. 1985. Calcium inactivates pyruvate dehydrogenase complex in brain mitochondria. Trans. Am. Soc. Neurochem. 16:193.Google Scholar
- 34.Linn, T. C., Pelley, J. W., Pettit, F. H., Hucho, F., Randall, D. D., and Reed, L. J. 1972. α-Keto acid dehydrogenase complexes: XV. Purification and properties of the component enzymes of the pyruvate dehydrogenase complexes from bovine kidney and heart. Arch. Biochem. Biophys. 148:327–342.PubMedGoogle Scholar