Towards the molecular basis for the regulation of mitochondrial dehydrogenases by calcium ions

  • Benjamin J. Nichols
  • Richard M. Denton
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 15)

Abstract

In mammalian cells, increases in calcium concentration cause increases in oxidative phosphorylation. This effect is mediated by the activation of four mitochondrial dehydrogenases by calcium ions; FAD-glycerol 3-phosphate dehydrogenase, pyruvate dehydrogenase, NAD-isocitrate dehydrogenase and oxoglutarate dehydrogenase. FAD-glycerol 3-phosphate dehydrogenase, being located on the outer surface of the inner mitochondrial membrane, is exposed to fluctuations in cytoplasmic calcium concentration. The other three enzymes are located within the mitochondrial matrix. While the kinetic properties of all of these enzymes are well characterised, the molecular basis for their regulation by calcium is not. This review uses information derived from calcium binding studies, analysis of conserved calcium binding motifs and comparison of amino acid sequences from calcium sensitive and non-sensitive enzymes to discuss how the recent cloning of several subunits from the four dehydrogenases enhances our understanding of the ways in which these enzymes bind calcium. FAD-glycerol 3-phosphate dehydrogenase binds calcium ions through a domain which is part of the polypeptide chain of the enzyme. In contrast, it is possible that the calcium sensitivity of the other three dehydrogenases may involve separate calcium binding subunits.

Key words

calcium mitochondria FAD-glycerol 3-phosphate dehydrogenase pyruvate dehydrogenase oxoglutarate dehydrogenase isocitrate dehydrogenase 

Abbreviations

GPDH

glycerol 3-phosphate dehydrogenase

PDH

pyruvate dehydrogenase

ICDH

isocitrate dehydrogenase

OGDH

oxoglutarate dehydrogenase

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Berridge MJ: Inositol trisphosphate and calcium signalling. Nature 361: 315–325, 1993PubMedCrossRefGoogle Scholar
  2. 2.
    Strynadka NCJ, James MNG: Crystal structure of the helix-loop-helix calcium binding proteins. Ann Rev Biochem 58: 951–998,1989PubMedCrossRefGoogle Scholar
  3. 3.
    Denton RM, McCormack JG: Calcium as a second messenger in the mitochondria of heart and other tissues. Ann Review Physiol 52: 451–466, 1990CrossRefGoogle Scholar
  4. 4.
    Hansford RG: Dehydrogenase activation by Ca2+ in cells and tissues. J Bioenerg Biomem 23: 823–830, 1991CrossRefGoogle Scholar
  5. 5.
    Aogaichi T, Evans J, Gabriel J, Plant GWE: The effects of calcium and lanthanum ions on the activity of bovine heart specific NAD-ICDH. Arch Biochem Biophys 195: 30–34,1980Google Scholar
  6. 6.
    Teague WM, Pettit FH, Wu T-L, Silberman SL, Reed LJ: Purification and properties of pyruvate dehydrogenase phosphatase from bovine heart and kidney. Biochemistry 21: 5585–5592, 1982PubMedCrossRefGoogle Scholar
  7. 7.
    Wernette ME, Ochs RS, Lardy HA: Ca2+ stimulation of rat liver mitochondrial glycerophosphate dehydrogenase. J Biol Chem 256:12767–12771, 1981PubMedGoogle Scholar
  8. 8.
    Rutter GA: Calcium binding to citrate cycle dehydrogenases. Int J Biochem 22:1081–1088, 1990PubMedCrossRefGoogle Scholar
  9. 9.
    Daveltov BA, S dhof TC: A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding. J Biol Chem 268: 26386–26390, 1993Google Scholar
  10. 10.
    Klee CB: Calcium dependent phospholipid and membrane binding proteins. Biochemistry 27: 6645–6650, 1988PubMedCrossRefGoogle Scholar
  11. 11.
    Burgoyne RD, Geisow MJ: The annexin family of calcium binding proteins. Cell Calcium 10:1–10, 1989PubMedCrossRefGoogle Scholar
  12. 12.
    Creutz CE: The annexins and exocytosis. Science 248: 924–931, 1992CrossRefGoogle Scholar
  13. 13.
    Huber R, Romisch J, Paques E: The crystal structure of human annexin V, an anticoagulant protein which binds to calcium and membranes. EMBO J 9: 37–3873–1990Google Scholar
  14. 14.
    Huber R, Schneider M, Romisch J, Paques E: The calcium binding sites in human annexin V by crystal structure analysis at 2.0 resolution. FEBS Lett 275: 15–21, 1990PubMedCrossRefGoogle Scholar
  15. 15.
    Huber R, Berendes R, Burger A, Schneider M, Karshikov A, Leucke H, Romisch J, Paques E: The crystal structure of human annexin V, after refinement. J Mol Biol 223: 683–690, 1992PubMedCrossRefGoogle Scholar
  16. 16.
    Sopkova J, Renouard M, Lewit-Bentley J: The crystal structure of a new high calcium form of annexin V. J Mol Biol 234: 816–825, 1994CrossRefGoogle Scholar
  17. 17.
    Bewley MC, Boustead CM, Walker J, Waller R, Huber R: Structure of chicken annexin V at 2.25 resolution. Biochemistry 32: 3923–3925, 1993PubMedCrossRefGoogle Scholar
  18. 18.
    Concha NO, Head JF, Kaetzel MA, Dedman JR, Seaton BA: Rat annexin V crystal structure: Ca2+-induced conformational changes. Science 261: 1321–1324 1993PubMedCrossRefGoogle Scholar
  19. 19.
    Weng X, Leucke H, Song I, Kang D, Kim S, Huber R: Crystal structure of human annexin I at 2.5 resolution. Prot Science 2: 448–458, 1993CrossRefGoogle Scholar
  20. 20.
    Oshara O, Tamaki K, Nakamura E, Tsuratu Y, Fujii Y, Shin M, Teraoka H, Okamoto M: Dog and rat pancreatic phospholipase A-2: complete amino acid sequence deduced from cDNAs. J Biochem 99: 733–739, 1986Google Scholar
  21. 21.
    Cole ES, Cyrus AL, Holohan PD, Fondy TP: Isolation and characterisation of flavin linked glycerol 3-phosphate dehydrogenase from rabbit skeletal muscle mitochondria and comparison with the enzyme from rabbit brain. J Biol Chem 253: 7952–7959, 1978PubMedGoogle Scholar
  22. 22.
    Trave G, Cregut D, Lionne C, Quignard J, Chiche L, Sri Widada J, Liautard J-P: Site directed mutagenesis of a calcium binding site modifies specifically the different biochemical properties of annexin I. Protein Engineering 7: 689–696, 1994PubMedCrossRefGoogle Scholar
  23. 23.
    Persechini A, Moncrief ND, Kretsinger RH: The EF-hand family of calcium-modulated proteins. Trends in Neuroscience, 12: 462–468, 1989CrossRefGoogle Scholar
  24. 24.
    Kretsinger RH: Calcium coordination and the calmodulin fold, divergent versus convergent evolution. Cold Spring Harbour Sym Quant Biol 52: 499–510, 1987CrossRefGoogle Scholar
  25. 25.
    Kretsinger RH, Nockolds CE: Carp muscle binding protein II Structure determination and general description. J Biol Chem 248: 3313–3326, 1973PubMedGoogle Scholar
  26. 26.
    Babu YS, Bugg CE, Cook WJ: Structure of calmodulin refined at 2.2. J Mol Biol 204: 191–204, 1988PubMedCrossRefGoogle Scholar
  27. 27.
    Herzberg O, James MNG: Structure of the calcium regulatory muscle protein troponin C at 2.8 resolution. Nature 313: 653–659, 1985PubMedCrossRefGoogle Scholar
  28. 28.
    Szebenyl DME, Moffat K: The refined structure of vitamin D-dependent calcium binding protein from bovine intestine. J Biol Chem 261: 8761–8767, 1986Google Scholar
  29. 29.
    Marsden BJ, Shaw GS, Sykes BD: Calcium binding proteins Elucidating the contributions to calcium affinity from an analysis of species variants and peptide fragments. Biochem Cell Biol 68: 257–262, 1990CrossRefGoogle Scholar
  30. 30.
    Potter JD, Johnson JD: In: W. Cheung (ed.). Calcium and cell function. Academic, New York Volume 2: 145–173, 1982Google Scholar
  31. 31.
    Ashley CC, Mulligan IP, Lea TJ: Calcium and activation mechanisms in skeletal muscle: Q Rev Biophys 24: 1–73, 1991PubMedCrossRefGoogle Scholar
  32. 32.
    Renner M, Danielson MA, Falke JF: Kinetic control of Ca2+ signalling: Tuning the ion dissociation rates of EF-hand Ca2+ binding sites. Proc Nat Acad Sci USA 90: 6493–6497, 1993PubMedCrossRefGoogle Scholar
  33. 33.
    Esterbrook RW, Sacktor B: A-Glycerophosphate oxidase of flight muscle mitochondria. J Biol Chem 233: 1014–1019, 1958Google Scholar
  34. 34.
    Garrib A, McMurray WC: Purification and characterisation of glycerol 3 phosphate dehydrogenase flavin-linked from rat liver mitochondria. J Biol Chem 261: 8042–8048, 1986PubMedGoogle Scholar
  35. 35.
    Hansford RG, Chappel JB: The effect of Ca2+ on the oxidation of glycerol phosphate by blowfly flight muscle mitochondria. Biochem Biophys Res Commun 27: 686–692, 1967PubMedCrossRefGoogle Scholar
  36. 36.
    Fisher AB, Scarpa A, LaNoue KF, Basset D, Williamson JR: Respiration of rat lung mitochondria and the influence of Ca2+ on substrate utilisation. Biochemistry 23: 1438–1446, 1973CrossRefGoogle Scholar
  37. 37.
    Brown LJ, Mac Donald MJ, Lehn DA, Moran SM: Sequence of rat mitochondrial glycerol-3-phospate cDNA. J Biol Chem 269: 14363–14366, 1994PubMedGoogle Scholar
  38. 38.
    Rutter GA, Pralong W-F, Wollheim CB: Regulation of mitochondrial glycerol-phospate dehydrogenase by Ca2+ within electropermeabilised insulin secreting cells INS-1. Biochim Biophys Acta 1175: 107–113, 1992PubMedCrossRefGoogle Scholar
  39. 39.
    Breen PJ, Johnson KA, Horrocks WD: Stopped-flow kinetic studies of metal ion dissociation or exchange in a tryptophan containing parvalbumin. Biochemistry 24: 4997–5004, 1985PubMedCrossRefGoogle Scholar
  40. 40.
    Roennow B, Keilland-Brandt MC: GUT2, a gene for mitochondrial glycerol 3-phosphate dehydrogenase from Saccharomyces cerevisiae. Yeast 9: 1121–1130, 1993CrossRefGoogle Scholar
  41. 41.
    Reed LJ: Regulation of mammalian pyruvate dehydrogenase complex by a phosphorylation-dephosphorylation cycle. Curr Top Cell Regul 18: 95–106, 1981PubMedGoogle Scholar
  42. 42.
    Denton RM, Randel PJ, Martin BR: Stimulation by calcium ions of pyruvate dehydrogenase phosphatase. Biochem J 128: 161–163, 1972PubMedGoogle Scholar
  43. 43.
    Thomas AP, Denton RM: Use of toluene permeabilised mitochndria to study the regulation of adipose tissue pyruvate dehydrogenase in situ. Biochem J 238: 83–91, 1986PubMedGoogle Scholar
  44. 44.
    Thomas AP, Diggle TA, Denton RM: Sensitivity of pyruvate dehydrogenase phospate phospatase to magnesium ions Similar effects of spermine and insulin. Biochem J 238: 93–101, 1986PubMedGoogle Scholar
  45. 45.
    Pettit FH, Roche TE, Reed LJ: Function of calcium ions in pyruvate dehydrogenase phosphatase activity. Biochem Biophys Res Commun 49: 563–571, 1972PubMedCrossRefGoogle Scholar
  46. 46.
    Davis PF, Pettit FH, Reed LJ: Peptides derived from pyruvate dehydrogenase as substrates for PDH kinase and phosphatase. Biochem Biophys Res Commun 75: 41–549, 1977CrossRefGoogle Scholar
  47. 47.
    Lawson JE, Niu X-D, Browning KS, Le Trong H, Yan J, Reed LJ: Molecular cloning and expression of the catalytic subunit of bovine pyruvate dehydrogenase phosphatase and sequence similarity with protein phosphatase 2C. Biochemistry 32: 8987–8993, 1993PubMedCrossRefGoogle Scholar
  48. 48.
    Koike K, Urata Y, Ohta S, Kawa Y, Koike M: Cloning and sequencing of cDNAs for the beta and alpha subunits of human pyruvate dehydrogenase. Proc Nat Acad Sci USA 85: 41–45, 1988PubMedCrossRefGoogle Scholar
  49. 49.
    Ramachandran N, Colman RF: Evidence for the presence of two non-identical subunits in NAD-isocitrate dehydrogenase of pig heart. Proc Natl Acad Sci USA 75: 252–255, 1978PubMedCrossRefGoogle Scholar
  50. 50.
    Ramachandran N, Colman RF: Chemical characterisation of distinct subunits of pig heart DPN-specific isocitrate dehydrogenase. J Biol Chem 255:8859–8864, 1980PubMedGoogle Scholar
  51. 51.
    Denton RM, Richards DA, Chin RJ: Calcium ions in the regulation of NAD-isocitrate dehydrogenase from the mitochondria of rat heart and other tissues. Biochem J 176: 899–906, 1978PubMedGoogle Scholar
  52. 52.
    McCormack JG, Denton RM: The effects of calcium ions andadenine nucleotides on the activity of pig heart 2-oxoglutarte dehydrogenase complex. Biochem J 180: 533–544, 1979PubMedGoogle Scholar
  53. 53.
    McCormack JG, Denton RM: A comparative study of the regulation by calcium of 2-oxoglutarte dehydrogenase and NAD-isocitrate dehydrogenase from a variety of sources. Biochem J 196: 619–624, 1981PubMedGoogle Scholar
  54. 54.
    Rutter GA, Denton RM: Regulation of NAD-linked isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase by calcium ions within toluene permeabilised rat mitochondria. Biochem J 252: 181–189, 1988PubMedGoogle Scholar
  55. 55.
    Rutter GA, Denton RM: The binding of Ca2+ ions to pig heart NAD-isocitrate dehydrogenase and the 2-oxoglutarate dehydrogenase complex. Biochem J 263: 453–62, 1989PubMedGoogle Scholar
  56. 56.
    Plaut GWE, Schramm VL, Aogaichi T: Action of magnesium ion on DPN linked isocitrate dehydrogenase from bovine heart. J Biol Chem 249: 1848–1856, 1974PubMedGoogle Scholar
  57. 57.
    Ehrlich RS, Colman RF: Dissimilar subunits of DPN-isocitrate dehydrogenase. J Biol Chem 258: 7079–7086, 1983PubMedGoogle Scholar
  58. 58.
    Barnes LD, Kuehn GD, Atkinson DE: Yeast DPN specific isocitrate dehydrogenase: purification and some properties. Biochemistry 10: 3939–3946, 1971PubMedCrossRefGoogle Scholar
  59. 59.
    Cupp JR, McAlister-Henn L: NAD-isocitrate dehydrogenase: cloning, disruption and nucleotide sequence of the IDH2 gene from Saccharomyces cerevisiae. J Biol Chem 266: 22199–22205, 1991PubMedGoogle Scholar
  60. 60.
    Cupp JR, McAlister-Henn L: Cloning and characterisation of the gene encoding IDH1 subunit of NAD-isocitrate dehydrogenase from Saccharomyces cerevisiae. J Biol Chem 267: 16417–16423, 1992PubMedGoogle Scholar
  61. 61.
    Nichols BJ, Rigoulet M, Denton RM: Comparison of the effects of Ca2+, adenine nucleotides and pH on the kinetic properties of mitochondrial NAD+-isocitrate dehydrogenase and oxoglutarate dehydrogenase from the yeast Saccharomyces cerevisiae and rat heart. Biochem J 303: 461–465, 1994PubMedGoogle Scholar
  62. 62.
    Nichols BJ, Hall L, Perry ACF; Denton RM: Molecular cloning and deduced amino acid sequences of the g-subunits of rat and monkey NAD+-isocitrate dehydrogenases. Biochem J 295: 347–350, 1993PubMedGoogle Scholar
  63. 63.
    Koike M, Koike K: Structure, assembly and function of mammalian a-keto acid dehydrogenase complexes. Adv Biophys 9: 187–227, 1976Google Scholar
  64. 64.
    Perham RN: Domains, motifs and linkers in 2-oxo acid dehydrogenase multienzyme complexes: a paradigm in the design of a multifunctional enzyme. Biochemistry 30: 8501–8512, 1991PubMedCrossRefGoogle Scholar
  65. 65.
    Lawlis VB, Roche TE: Inhibition of bovine kidney a-ketoglutarate dehydrogenase by NAD in the presence or absence of calcium ion and effect of ADP on NAD inhibition. Biochemistry 20: 2523–2527, 1981Google Scholar
  66. 66.
    Rutter GA, Leake MJ, McCormack JG, Denton RM: Role of Ca2+ and Mg2+ in the control of pyruvate and 2-oxoglutarate dehydrogenase complexes. In: H. Bisswanger and J. Ullrich (eds). Proceedings of the Third International Meeting on The Function of Thiamine Diphosphate Enzymes, VCH Ltd, 1991Google Scholar
  67. 67.
    Walsh DA, Cooper RH, Denton RM, Bridges BJ, Randle RM: The elementary reactions of the pig heart pyruvate dehydrogenase complex A study of the inhibition by phosphorylation. Biochem J 157: 41–46,1976PubMedGoogle Scholar
  68. 68.
    Koike K, Urata Y, Goto S: Cloning and nucleotide sequence of the cDNA encoding human 2-oxoglutarate dehydrogenase (lipoamide). Proc Nat Acad Sci USA 89: 1963–1967, 1992PubMedCrossRefGoogle Scholar
  69. 69.
    Repetto B, Tzagoloff A: Structure and regulation of KGD1, the structural gene for yeast a-ketoglutarate dehydrogenase. Mol Cell Biol 9: 2695–2705, 1989PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1995

Authors and Affiliations

  • Benjamin J. Nichols
    • 1
  • Richard M. Denton
    • 1
  1. 1.Department of Biochemistry, School of Medical SciencesUniversity of BristolBristolUK

Personalised recommendations