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PMID: 8569730 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

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

Molecular and cellular biochemistry ·Vol. 149-150 ·1995-00-00 ·Pages 203-12

Nichols BJ, Denton RM

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.

MeSH Terms
Amino Acid Sequence Animals Annexins/chemistry,metabolism Calcium/physiology Calcium-Binding Proteins/chemistry Consensus Sequence Glycerolphosphate Dehydrogenase/metabolism Isocitrate Dehydrogenase/metabolism Ketoglutarate Dehydrogenase Complex/metabolism Mitochondria/enzymology Models, Molecular Molecular Sequence Data Protein Structure, Tertiary Pyruvate Dehydrogenase Complex/metabolism Rats Saccharomyces cerevisiae/enzymology Sequence Alignment Sequence Homology, Amino Acid
Chemicals
Annexins Calcium-Binding Proteins Pyruvate Dehydrogenase Complex Glycerolphosphate Dehydrogenase Isocitrate Dehydrogenase Ketoglutarate Dehydrogenase Complex Calcium
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Nichols B J
Department of Biochemistry, School of Medical Sciences, University of Bristol, UK.
Denton R M
References (67)
67 references, click to expand
  1. Structure of calmodulin refined at 2.2 A resolution.
    J Mol Biol. 1988 Nov 5;204(1):191-204 PMID: 3145979
  2. Purification and characterization of glycerol-3-phosphate dehydrogenase (flavin-linked) from rat liver mitochondria.
    J Biol Chem. 1986 Jun 15;261(17):8042-8 PMID: 3711123
  3. Calcium ions and the regulation of NAD+-linked isocitrate dehydrogenase from the mitochondria of rat heart and other tissues.
    Biochem J. 1978 Dec 15;176(3):899-906 PMID: 218557
  4. Cloning and characterization of the gene encoding the IDH1 subunit of NAD(+)-dependent isocitrate dehydrogenase from Saccharomyces cerevisiae.
    J Biol Chem. 1992 Aug 15;267(23):16417-23 PMID: 1644826
  5. Site-directed mutagenesis of a calcium binding site modifies specifically the different biochemical properties of annexin I.
    Protein Eng. 1994 May;7(5):689-96 PMID: 7915419
  6. Carp muscle calcium-binding protein. II. Structure determination and general description.
    J Biol Chem. 1973 May 10;248(9):3313-26 PMID: 4700463
  7. Molecular cloning and deduced amino acid sequences of the gamma-subunits of rat and monkey NAD(+)-isocitrate dehydrogenases.
    Biochem J. 1993 Oct 15;295 ( Pt 2):347-50 PMID: 8240232
  8. Action of magnesium ion on diphosphopyridine nucleotide-linked isocitrate dehydrogenase from bovine heart. Characterization of the forms of the substrate and the modifier of the reaction.
    J Biol Chem. 1974 Mar 25;249(6):1848-56 PMID: 4361827
  9. Regulation of mammalian pyruvate dehydrogenase complex by a phosphorylation-dephosphorylation cycle.
    Curr Top Cell Regul. 1981;18:95-106 PMID: 7273851
  10. Chemical characterization of distinct subunits of pig heart DPN-specific isocitrate dehydrogenase.
    J Biol Chem. 1980 Sep 25;255(18):8859-64 PMID: 7410398
  11. Kinetic control of Ca(II) signaling: tuning the ion dissociation rates of EF-hand Ca(II) binding sites.
    Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6493-7 PMID: 8341660
  12. The refined structure of vitamin D-dependent calcium-binding protein from bovine intestine. Molecular details, ion binding, and implications for the structure of other calcium-binding proteins.
    J Biol Chem. 1986 Jul 5;261(19):8761-77 PMID: 3722173
  13. Ca2+-dependent phospholipid- (and membrane-) binding proteins.
    Biochemistry. 1988 Sep 6;27(18):6645-53 PMID: 2973805
  14. Ca2+ stimulation of rat liver mitochondrial glycerophosphate dehydrogenase.
    J Biol Chem. 1981 Dec 25;256(24):12767-71 PMID: 6796576
  15. Stopped-flow kinetic studies of metal ion dissociation or exchange in a tryptophan-containing parvalbumin.
    Biochemistry. 1985 Sep 10;24(19):4997-5004 PMID: 4074672
  16. Cloning and sequencing of cDNAs encoding alpha and beta subunits of human pyruvate dehydrogenase.
    Proc Natl Acad Sci U S A. 1988 Jan;85(1):41-5 PMID: 3422424
  17. Structure and regulation of KGD1, the structural gene for yeast alpha-ketoglutarate dehydrogenase.
    Mol Cell Biol. 1989 Jun;9(6):2695-705 PMID: 2503710
  18. Calcium binding proteins. Elucidating the contributions to calcium affinity from an analysis of species variants and peptide fragments.
    Biochem Cell Biol. 1990 Mar;68(3):587-601 PMID: 2198059
  19. Isolation and characterization of flavin-linked glycerol-3-phosphate dehydrogenase from rabbit skeletal muscle mitochondria and comparison with the enzyme from rabbit brain.
    J Biol Chem. 1978 Nov 10;253(21):7952-9 PMID: 701295
  20. Inhibition of bovine kidney alpha-ketoglutarate dehydrogenase complex by reduced nicotinamide adenine dinucleotide in the presence or absence of calcium ion and effect of adenosine 5'-diphosphate on reduced nicotinamide adenine dinucleotide inhibition.
    Biochemistry. 1981 Apr 28;20(9):2519-24 PMID: 6894547
  21. Separation, recombination, and characterization of dissimilar subunits of the DPN-dependent isocitrate dehydrogenase from pig heart.
    J Biol Chem. 1983 Jun 10;258(11):7079-86 PMID: 6853513
  22. The binding of Ca2+ ions to pig heart NAD+-isocitrate dehydrogenase and the 2-oxoglutarate dehydrogenase complex.
    Biochem J. 1989 Oct 15;263(2):453-62 PMID: 2597117
  23. Dog and rat pancreatic phospholipases A2: complete amino acid sequences deduced from complementary DNAs.
    J Biochem. 1986 Mar;99(3):733-9 PMID: 3754861
  24. Peptides derived from pyruvate dehydrogenase as substrates for pyruvate dehydrogenase kinase and phosphatase.
    Biochem Biophys Res Commun. 1977 Apr 11;75(3):541-9 PMID: 193491
  25. The elementary reactions of the pig heart pyruvate dehydrogenase complex. A study of the inhibition by phosphorylation.
    Biochem J. 1976 Jul 1;157(1):41-67 PMID: 183746
  26. Ca2+ and activation mechanisms in skeletal muscle.
    Q Rev Biophys. 1991 Feb;24(1):1-73 PMID: 2047521
  27. Function of calcium ions in pyruvate dehydrogenase phosphatase activity.
    Biochem Biophys Res Commun. 1972 Oct 17;49(2):563-71 PMID: 4344895
  28. The crystal and molecular structure of human annexin V, an anticoagulant protein that binds to calcium and membranes.
    EMBO J. 1990 Dec;9(12):3867-74 PMID: 2147412
  29. The effect of Ca2+ on the oxidation of glycerol phosphate by blowfly flight-muscle mitochondria.
    Biochem Biophys Res Commun. 1967 Jun 23;27(6):686-92 PMID: 4964598
  30. Sequence of rat mitochondrial glycerol-3-phosphate dehydrogenase cDNA. Evidence for EF-hand calcium-binding domains.
    J Biol Chem. 1994 May 20;269(20):14363-6 PMID: 8182039
  31. A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding.
    J Biol Chem. 1993 Dec 15;268(35):26386-90 PMID: 8253763
  32. Ca2+ as a second messenger within mitochondria of the heart and other tissues.
    Annu Rev Physiol. 1990;52:451-66 PMID: 2184763
  33. Crystal structure of human annexin I at 2.5 A resolution.
    Protein Sci. 1993 Mar;2(3):448-58 PMID: 8453382
  34. Rat annexin V crystal structure: Ca(2+)-induced conformational changes.
    Science. 1993 Sep 3;261(5126):1321-4 PMID: 8362244
  35. Use of toluene-permeabilized mitochondria to study the regulation of adipose tissue pyruvate dehydrogenase in situ. Further evidence that insulin acts through stimulation of pyruvate dehydrogenase phosphate phosphatase.
    Biochem J. 1986 Aug 15;238(1):93-101 PMID: 3026348
  36. Dehydrogenase activation by Ca2+ in cells and tissues.
    J Bioenerg Biomembr. 1991 Dec;23(6):823-54 PMID: 1778993
  37. Regulation of mitochondrial glycerol-phosphate dehydrogenase by Ca2+ within electropermeabilized insulin-secreting cells (INS-1).
    Biochim Biophys Acta. 1992 Dec 15;1175(1):107-13 PMID: 1482691
  38. GUT2, a gene for mitochondrial glycerol 3-phosphate dehydrogenase of Saccharomyces cerevisiae.
    Yeast. 1993 Oct;9(10):1121-30 PMID: 8256521
  39. Ca2(+)-binding to citrate cycle dehydrogenases.
    Int J Biochem. 1990;22(10 ):1081-8 PMID: 2289614
  40. Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase.
    Biochem J. 1972 Jun;128(1):161-3 PMID: 4343661
  41. Cloning and nucleotide sequence of the cDNA encoding human 2-oxoglutarate dehydrogenase (lipoamide).
    Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1963-7 PMID: 1542694
  42. Sensitivity of pyruvate dehydrogenase phosphate phosphatase to magnesium ions. Similar effects of spermine and insulin.
    Biochem J. 1986 Aug 15;238(1):83-91 PMID: 3026347
  43. NAD(+)-dependent isocitrate dehydrogenase. Cloning, nucleotide sequence, and disruption of the IDH2 gene from Saccharomyces cerevisiae.
    J Biol Chem. 1991 Nov 25;266(33):22199-205 PMID: 1939242
  44. Purification and properties of pyruvate dehydrogenase phosphatase from bovine heart and kidney.
    Biochemistry. 1982 Oct 26;21(22):5585-92 PMID: 6293549
  45. The crystal structure of a new high-calcium form of annexin V.
    J Mol Biol. 1993 Dec 5;234(3):816-25 PMID: 8254674
  46. The annexin family of calcium-binding proteins. Review article.
    Cell Calcium. 1989 Jan;10(1):1-10 PMID: 2659190
  47. Crystal and molecular structure of human annexin V after refinement. Implications for structure, membrane binding and ion channel formation of the annexin family of proteins.
    J Mol Biol. 1992 Feb 5;223(3):683-704 PMID: 1311770
  48. The calcium binding sites in human annexin V by crystal structure analysis at 2.0 A resolution. Implications for membrane binding and calcium channel activity.
    FEBS Lett. 1990 Nov 26;275(1-2):15-21 PMID: 2148156
  49. The annexins and exocytosis.
    Science. 1992 Nov 6;258(5084):924-31 PMID: 1439804
  50. Respiration of rat lung mitochondria and the influence of Ca 2+ on substrate utilization.
    Biochemistry. 1973 Mar 27;12(7):1438-45 PMID: 4348834
  51. Structure, assembly and function of mammalian alpha-keto acid dehydrogenase complexes.
    Adv Biophys. 1976;:187-227 PMID: 797242
  52. Yeast diphosphopyridine nucleotide specific isocitrate dehydrogenase. Purification and some properties.
    Biochemistry. 1971 Oct 12;10(21):3939-44 PMID: 4334283
  53. The EF-hand family of calcium-modulated proteins.
    Trends Neurosci. 1989 Nov;12(11):462-7 PMID: 2479149
  54. Structure of chicken annexin V at 2.25-A resolution.
    Biochemistry. 1993 Apr 20;32(15):3923-9 PMID: 8471604
  55. 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. 1994 Oct 15;303 ( Pt 2):461-5 PMID: 7980405
  56. Evidence for the presence of two nonidentical subunits in NAD-dependent isocitrate dehydrogenase of pig heart.
    Proc Natl Acad Sci U S A. 1978 Jan;75(1):252-5 PMID: 203934
  57. The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex.
    Biochem J. 1979 Jun 15;180(3):533-44 PMID: 39549
  58. Molecular cloning and expression of the catalytic subunit of bovine pyruvate dehydrogenase phosphatase and sequence similarity with protein phosphatase 2C.
    Biochemistry. 1993 Sep 7;32(35):8987-93 PMID: 8396421
  59. A comparative study of the regulation of Ca2+ of the activities of the 2-oxoglutarate dehydrogenase complex and NAD+-isocitrate dehydrogenase from a variety of sources.
    Biochem J. 1981 May 15;196(2):619-24 PMID: 7032511
  60. Regulation of NAD+-linked isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase by Ca2+ ions within toluene-permeabilized rat heart mitochondria. Interactions with regulation by adenine nucleotides and NADH/NAD+ ratios.
    Biochem J. 1988 May 15;252(1):181-9 PMID: 3421900
  61. Crystal structures of the helix-loop-helix calcium-binding proteins.
    Annu Rev Biochem. 1989;58:951-98 PMID: 2673026
  62. Domains, motifs, and linkers in 2-oxo acid dehydrogenase multienzyme complexes: a paradigm in the design of a multifunctional protein.
    Biochemistry. 1991 Sep 3;30(35):8501-12 PMID: 1888719
  63. Inositol trisphosphate and calcium signalling.
    Nature. 1993 Jan 28;361(6410):315-25 PMID: 8381210
  64. Structure of the calcium regulatory muscle protein troponin-C at 2.8 A resolution.
    Nature. 1985 Feb 21-27;313(6004):653-9 PMID: 3974698
  65. alpha-Glycerophosphate oxidase of flight muscle mitochondria.
    J Biol Chem. 1958 Oct;233(4):1014-9 PMID: 13587533
  66. The effects of calcium and lanthanide ions on the activity of bovine heart nicotinamide adenine dinucleotide-specific isocitrate dehydrogenase.
    Arch Biochem Biophys. 1980 Oct 1;204(1):350-6 PMID: 6775600
  67. Calcium coordination and the calmodulin fold: divergent versus convergent evolution.
    Cold Spring Harb Symp Quant Biol. 1987;52:499-510 PMID: 3454274
Article Info
Journal
Molecular and cellular biochemistry
Abbr.
Mol Cell Biochem
ISSN
0300-8177
DOI
10.1007/BF01076578
Published
1995-00-00
Pages
203-12
Language
English
Region
Netherlands
NLM ID
0364456
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1007/BF01076578 View journal details
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