Abstract
In the heart and other mammalian tissues, there are three exclusively intramitochondrial dehydrogenases that occupy key regulatory sites in oxidative metabolism which can be activated by increases in Ca2+ in the approximate range 0.05–5 μM; they are the pyruvate, NAD+-isocitrate and 2-oxoglutarate dehydrogenases. Activation of these enzymes can be demonstrated within intact mitochondria, incubated under expected physiological conditions, when the extramitochondrial concentration of Ca+ is raised within the expected physiological range. Recent studies with fura-2-loaded mitochondria have established that matrix Ca2+ is indeed in the 0.02–2 μM range as the enzymes are activated. There is now good evidence that in the rat heart, increases in cytoplasmic [Ca2+] caused by various inotropic agents result in increases in intramitochondrial Ca2+ and activation of these dehydrogenases. It is argued therefore that matrix Ca2+ may thus be a key regulator of oxidative phosphorylation under such circumstances. The major advantage of such a mechanism of dehydrogenase-based control of this process would be to the energy homeostasis of the cell by allowing stimulated ATP production without the need to decrease the ATP/ADP ratio. Therefore it is also proposed that the major function of the mitochondrial Ca2+-transport system is to regulate matrix Ca2+, and that the ability of mitochondria to buffer the extramitochondrial concentration of Ca2+ may thus only be reserved for pathophysiological conditions of abnormal sarcolemmal Ca2+ influx as perhaps may occur in ischaemia reperfusion.
Similar content being viewed by others
References
Katz LA, Koretsky AP, Balaban, RS: Respiratory control in the glucose perfused heart. A31P NMR and NADH fluorescence study. FEBS Lett 221: 270–276, 1987
Denton RM, McCormack JG: Ca2+ transport by mammalian mitochondria and its role in hormone action. Am J Physiol 249: E543-E554, 1985
Hansford RG: Relation between mitochondrial calcium transport and control of energy metabolism. Rev Physiol Biochem Pharmacol 102: 1–72, 1985
McCormack JG, Denton RM: Ca2+ as a second messenger within mitochondria. Trends Biochem Sci 11: 258–262, 1986
Wendt-Gallitelli MF: Ca-pools involved in the regulation of cardiac contraction under positive inotropy. X-ray microanalysis of rapidly-frozen ventricular muscle of guinea-pig. Basic Res Cardiol 81: 25–32, 1986
denton RM, McCormack JG, Edgell NJ: Role of calcium ions in the regulation of intramitochondrial metabolism. Effects of Na+, Mg2+ and ruthenium red on the Ca2+-stimulated oxidation of oxoglutarate and on pyruvate dehydrogenase activity in intact rat heart mitochondria. Biochem J 190: 107–117, 1980
Lukacs GL, Kapus A, Fonyo A: Parallel measurement of oxoglutarate dehydrogenase activity and matrix free Ca2+ in fura-2-loaded heart mitochondria. FEBS Lett 229: 219–223, 1988
McCormack JG, Browne HM, Dawes NJ.: Studies on mitochondrial Ca2+-transport and matrix Ca2+ using fura-2-loaded rat heart mitochondria. Biochim Biophys Acta 973: 420–427, 1989
Crompton M: The regulation of mitochondrial calcium transport in heart. Curr Top Membr Transp 25: 231–276, 1985
McCormack JG, England PJ: Ruthenium red inhibits the activation of pyruvate dehydrogenase caused by positive inotropic agents in the perfused rat heart. Biochem J 214: 581–585, 1983
Hansford RG: Relation between cytosolic free Ca2+ concentration and the control of pyruvate dehydrogenase in isolated cardiac myocytes. Biochem J 241: 145–151, 1987
Crompton M, Kessar P, Al-Nasser I: The α-adrenergic mediated activation of the cardiac mitochondrial Ca2+ uniporter and its role in the control of intramitochondrial Ca2+ in vivo. Biochem J 216: 333–342, 1983
McCormack JG, Denton RM: Role of Ca2+ ions in the regulation of intramitochondrial metabolism in rat heart. Evidence from studies with isolated mitochondria that adrenaline activates the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes by increasing the intramitochondrial concentration of Ca2+. Biochem J 218: 235–247, 1984
Nicholls DG, Akerman KEO: Mitochondrial calcium transport. Biochim Biophys Acta 683: 57–88, 1982
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
McCormack, J.G., Denton, R.M. The role of Ca2+ ions in the regulation of intramitochondrial metabolism and energy production in rat heart. Mol Cell Biochem 89, 121–125 (1989). https://doi.org/10.1007/BF00220763
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00220763