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Mechanisms of Bioenergy Production in Mitochondria

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Mitochondria and Their Role in Cardiovascular Disease
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Abstract

The majority of the cellular energy is produced in the form of ATP by the oxidative phosphorylation (OXPHOS) pathway, through the oxidation of organic substrates, mainly carbohydrates and fatty acids. Carbohydrates initially undergo conversion into pyruvate via glycolysis. Pyruvate then enters mitochondria and transforms to acetyl-CoA by the mitochondrial pyruvate dehydrogenase complex for further oxidation in the tricarboxylic acid (TCA) cycle. Fatty acids also translocate to mitochondria for β-oxidation. Analogous to carbohydrate metabolism, the end product of fatty acid β-oxidation is acetyl-CoA. This intermediary metabolite is “burned” to carbon dioxide via cascade of enzymatic reactions, known as the TCA (or Krebs) cycle to produce high-energy reducing equivalents, in the form of NADH and FADH2. Oxidation of NADH and FADH2 is a series of redox reactions catalyzed by components of mitochondrial respiratory electron transport chain (ETC). High-energy electrons, released from oxidized reducing equivalents, flow through the respiratory chain and finally reduce molecular oxygen-generating molecules of water. Energy of electrons is transformed into the electrochemical gradient of protons across mitochondrial inner membrane, which is utilized by ATP synthase to phosphorylate ADP into ATP. Several mitochondrial kinases orchestrate coupling of ATP synthesis (in mitochondria) with ATP utilization (in different cell compartments).

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References

  1. Hildyard JC, Halestrap AP. Identification of the mitochondrial pyruvate carrier in Saccharomyces cerevisiae. Biochem J. 2003;374(Pt 3):607–11.

    PubMed  CAS  Google Scholar 

  2. Hildyard JC, Ammala C, Dukes ID, Thomson SA, Halestrap AP. Identification and characterisation of a new class of highly specific and potent inhibitors of the mitochondrial pyruvate carrier. Biochim Biophys Acta. 2005;1707(2–3):221–30.

    PubMed  CAS  Google Scholar 

  3. Hiromasa Y, Fujisawa T, Aso Y, Roche TE. Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components. J Biol Chem. 2004;279(8):6921–33.

    PubMed  CAS  Google Scholar 

  4. Roche TE, Baker JC, Yan X, et al. Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Prog Nucleic Acid Res Mol Biol. 2001;70:33–75.

    PubMed  CAS  Google Scholar 

  5. Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM. Diversity of the pyruvate dehydrogenase kinase gene family in humans. J Biol Chem. 1995;270(48):28989–94.

    PubMed  CAS  Google Scholar 

  6. Rowles J, Scherer SW, Xi T, et al. Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. J Biol Chem. 1996;271(37):22376–82.

    PubMed  CAS  Google Scholar 

  7. Kato M, Chuang JL, Tso SC, Wynn RM, Chuang DT. Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex. EMBO J. 2005;24(10):1763–74.

    PubMed  CAS  Google Scholar 

  8. Knoechel TR, Tucker AD, Robinson CM, et al. Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry. 2006;45(2):402–15.

    PubMed  CAS  Google Scholar 

  9. Bao H, Kasten SA, Yan X, Roche TE. Pyruvate dehydrogenase kinase isoform 2 activity limited and further inhibited by slowing down the rate of dissociation of ADP. Biochemistry. 2004;43(42):13432–41.

    PubMed  CAS  Google Scholar 

  10. Huang B, Gudi R, Wu P, Harris RA, Hamilton J, Popov KM. Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation. J Biol Chem. 1998;273(28):17680–8.

    PubMed  CAS  Google Scholar 

  11. Lawson JE, Niu XD, Browning KS, Trong HL, 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. 1993;32(35):8987–93.

    PubMed  CAS  Google Scholar 

  12. Larner J, Huang LC, Suzuki S, et al. Insulin mediators and the control of pyruvate dehydrogenase complex. Ann N Y Acad Sci. 1989;573:297–305.

    PubMed  CAS  Google Scholar 

  13. Larner J, Price JD, Heimark D, et al. Isolation, structure, synthesis, and bioactivity of a novel putative insulin mediator. A galactosamine chiro-inositol pseudo-disaccharide Mn2+ chelate with insulin-like activity. J Med Chem. 2003;46(15):3283–91.

    PubMed  CAS  Google Scholar 

  14. Caruso M, Maitan MA, Bifulco G, et al. Activation and mitochondrial translocation of protein kinase Cdelta are necessary for insulin stimulation of pyruvate dehydrogenase complex activity in muscle and liver cells. J Biol Chem. 2001;276(48):45088–97.

    PubMed  CAS  Google Scholar 

  15. Denton RM, Midgley PJ, Rutter GA, Thomas AP, McCormack JG. Studies into the mechanism whereby insulin activates pyruvate dehydrogenase complex in adipose tissue. Ann N Y Acad Sci. 1989;573:285–96.

    PubMed  CAS  Google Scholar 

  16. Thomas AP, Denton RM. 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;238(1):93–101.

    PubMed  CAS  Google Scholar 

  17. Lawson JE, Park SH, Mattison AR, Yan J, Reed LJ. Cloning, expression, and properties of the regulatory subunit of bovine pyruvate dehydrogenase phosphatase. J Biol Chem. 1997;272(50):31625–9.

    PubMed  CAS  Google Scholar 

  18. Chen G, Wang L, Liu S, Chuang C, Roche TE. Activated function of the pyruvate dehydrogenase phosphatase through Ca2+-facilitated binding to the inner lipoyl domain of the dihydrolipoyl acetyltransferase. J Biol Chem. 1996;271(45):28064–70.

    PubMed  CAS  Google Scholar 

  19. Hansford RG. Studies on the effects of coenzyme A-SH: acetyl coenzyme A, nicotinamide adenine dinucleotide: reduced nicotinamide adenine dinucleotide, and adenosine diphosphate: adenosine triphosphate ratios on the interconversion of active and inactive pyruvate dehydrogenase in isolated rat heart mitochondria. J Biol Chem. 1976;251(18):5483–9.

    PubMed  CAS  Google Scholar 

  20. Pettit FH, Pelley JW, Reed LJ. Regulation of pyruvate dehydrogenase kinase and phosphatase by acetyl-CoA/CoA and NADH/NAD ratios. Biochem Biophys Res Commun. 1975;65(2):575–82.

    PubMed  CAS  Google Scholar 

  21. Pratt ML, Roche TE. Mechanism of pyruvate inhibition of kidney pyruvate dehydrogenasea kinase and synergistic inhibition by pyruvate and ADP. J Biol Chem. 1979;254(15):7191–6.

    PubMed  CAS  Google Scholar 

  22. Kerner J, Hoppel C. Fatty acid import into mitochondria. Biochim Biophys Acta. 2000;1486(1):1–17.

    PubMed  CAS  Google Scholar 

  23. Ramsay RR, Gandour RD, van der Leij FR. Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta. 2001;1546(1):21–43.

    PubMed  CAS  Google Scholar 

  24. Price N, van der Leij F, Jackson V, et al. A novel brain-expressed protein related to carnitine palmitoyltransferase I. Genomics. 2002;80(4):433–42.

    PubMed  CAS  Google Scholar 

  25. Brown NF, Weis BC, Husti JE, Foster DW, McGarry JD. Mitochondrial carnitine palmitoyltransferase I isoform switching in the developing rat heart. J Biol Chem. 1995;270(15):8952–7.

    PubMed  CAS  Google Scholar 

  26. Lavrentyev EN, Matta SG, Cook GA. Expression of three carnitine palmitoyltransferase-I isoforms in 10 regions of the rat brain during feeding, fasting, and diabetes. Biochem Biophys Res Commun. 2004;315(1):174–8.

    PubMed  CAS  Google Scholar 

  27. Moczulski D, Majak I, Mamczur D. An overview of beta-oxidation disorders. Postepy Hig Med Dosw (Online). 2009;63:266–77.

    Google Scholar 

  28. Andresen BS, Dobrowolski SF, O’Reilly L, et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001;68(6):1408–18.

    PubMed  CAS  Google Scholar 

  29. Gregersen N, Bross P, Andresen BS. Genetic defects in fatty acid beta-oxidation and acyl-CoA dehydrogenases. Molecular pathogenesis and genotype-phenotype relationships. Eur J Biochem. 2004;271(3):470–82.

    PubMed  CAS  Google Scholar 

  30. Vianey-Saban C, Divry P, Brivet M, et al. Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta. 1998;269(1):43–62.

    PubMed  CAS  Google Scholar 

  31. Wanders RJ, Duran M, Ijlst L, et al. Sudden infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase. Lancet. 1989;2(8653):52–3.

    PubMed  CAS  Google Scholar 

  32. Yang Z, Zhao Y, Bennett MJ, Strauss AW, Ibdah JA. Fetal genotypes and pregnancy outcomes in 35 families with mitochondrial trifunctional protein mutations. Am J Obstet Gynecol. 2002;187(3):715–20.

    PubMed  CAS  Google Scholar 

  33. Ofman R, Ruiter JP, Feenstra M, et al. 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene. Am J Hum Genet. 2003;72(5):1300–7.

    PubMed  CAS  Google Scholar 

  34. Tieu K, Perier C, Vila M, et al. L-3-hydroxyacyl-CoA dehydrogenase II protects in a model of Parkinson’s disease. Ann Neurol. 2004;56(1):51–60.

    PubMed  CAS  Google Scholar 

  35. Yang SY, He XY. Role of type 10 17beta-hydroxysteroid dehydrogenase in the pathogenesis of Alzheimer’s disease. Adv Exp Med Biol. 2001;487:101–10.

    PubMed  CAS  Google Scholar 

  36. Chinopoulos C, Tretter L, Adam-Vizi V. Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals: inhibition of alpha-ketoglutarate dehydrogenase. J Neurochem. 1999;73(1):220–8.

    PubMed  CAS  Google Scholar 

  37. Andersson U, Leighton B, Young ME, Blomstrand E, Newsholme EA. Inactivation of aconitase and oxoglutarate dehydrogenase in skeletal muscle in vitro by superoxide anions and/or nitric oxide. Biochem Biophys Res Commun. 1998;249(2):512–6.

    PubMed  CAS  Google Scholar 

  38. Brazzolotto X, Gaillard J, Pantopoulos K, Hentze MW, Moulis JM. Human cytoplasmic aconitase (Iron regulatory protein 1) is converted into its [3Fe-4S] form by hydrogen peroxide in vitro but is not activated for iron-responsive element binding. J Biol Chem. 1999;274(31):21625–30.

    PubMed  CAS  Google Scholar 

  39. Bulteau AL, Ikeda-Saito M, Szweda LI. Redox-dependent modulation of aconitase activity in intact mitochondria. Biochemistry. 2003;42(50):14846–55.

    PubMed  CAS  Google Scholar 

  40. Yarian CS, Toroser D, Sohal RS. Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice. Mech Ageing Dev. 2006;127(1):79–84.

    PubMed  CAS  Google Scholar 

  41. Nichols BJ, Hall L, Perry AC, Denton RM. Molecular cloning and deduced amino acid sequences of the gamma-subunits of rat and monkey NAD(+)-isocitrate dehydrogenases. Biochem J. 1993;295(Pt 2):347–50.

    PubMed  CAS  Google Scholar 

  42. Nichols BJ, Perry AC, Hall L, Denton RM. Molecular cloning and deduced amino acid sequences of the alpha- and beta- subunits of mammalian NAD(+)-isocitrate dehydrogenase. Biochem J. 1995;310(Pt 3):917–22.

    PubMed  CAS  Google Scholar 

  43. Bzymek KP, Colman RF. Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase. Biochemistry. 2007;46(18):5391–7.

    PubMed  CAS  Google Scholar 

  44. Soundar S, O’Hagan M, Fomulu KS, Colman RF. Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase. J Biol Chem. 2006;281(30):21073–81.

    PubMed  CAS  Google Scholar 

  45. Denton RM, Richards DA, Chin JG. Calcium ions and the regulation of NAD+-linked isocitrate dehydrogenase from the mitochondria of rat heart and other tissues. Biochem J. 1978;176(3):899–906.

    PubMed  CAS  Google Scholar 

  46. Rutter GA, Denton RM. 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;252(1):181–9.

    PubMed  CAS  Google Scholar 

  47. Hoek JB, Rydstrom J. Physiological roles of nicotinamide nucleotide transhydrogenase. Biochem J. 1988;254(1):1–10.

    PubMed  CAS  Google Scholar 

  48. Sazanov LA, Jackson JB. Proton-translocating transhydrogenase and NAD- and NADP-linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria. FEBS Lett. 1994;344(2–3):109–16.

    PubMed  CAS  Google Scholar 

  49. Graham LD, Packman LC, Perham RN. Kinetics and specificity of reductive acylation of lipoyl domains from 2-oxo acid dehydrogenase multienzyme complexes. Biochemistry. 1989;28(4):1574–81.

    PubMed  CAS  Google Scholar 

  50. Lawlis VB, Roche TE. Regulation of bovine kidney alpha-ketoglutarate dehydrogenase complex by calcium ion and adenine nucleotides. Effects on S0.5 for alpha-ketoglutarate. Biochemistry. 1981;20(9):2512–8.

    PubMed  CAS  Google Scholar 

  51. McCartney RG, Rice JE, Sanderson SJ, Bunik V, Lindsay H, Lindsay JG. Subunit interactions in the mammalian alpha-ketoglutarate dehydrogenase complex. Evidence for direct association of the alpha-ketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components. J Biol Chem. 1998;273(37):24158–64.

    PubMed  CAS  Google Scholar 

  52. Yeaman SJ. The 2-oxo acid dehydrogenase complexes: recent advances. Biochem J. 1989;257(3):625–32.

    PubMed  CAS  Google Scholar 

  53. Lucas DT, Szweda LI. Declines in mitochondrial respiration during cardiac reperfusion: age-dependent inactivation of alpha-ketoglutarate dehydrogenase. Proc Natl Acad Sci USA. 1999;96(12):6689–93.

    PubMed  CAS  Google Scholar 

  54. Bunik VI, Sievers C. Inactivation of the 2-oxo acid dehydrogenase complexes upon generation of intrinsic radical species. Eur J Biochem. 2002;269(20):5004–15.

    PubMed  CAS  Google Scholar 

  55. Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med. 1995;19(2):227–50.

    PubMed  CAS  Google Scholar 

  56. Yankovskaya V, Horsefield R, Tornroth S, et al. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science. 2003;299(5607):700–4.

    PubMed  CAS  Google Scholar 

  57. Sun F, Huo X, Zhai Y, et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005;121(7):1043–57.

    PubMed  CAS  Google Scholar 

  58. Hagerhall C. Succinate: quinone oxidoreductases. Variations on a conserved theme. Biochim Biophys Acta. 1997;1320(2):107–41.

    PubMed  CAS  Google Scholar 

  59. Cimen H, Han MJ, Yang Y, Tong Q, Koc H, Koc EC. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry. 2010;49(2):304–11.

    PubMed  CAS  Google Scholar 

  60. Tomitsuka E, Kita K, Esumi H. Regulation of succinate-ubiquinone reductase and fumarate reductase activities in human complex II by phosphorylation of its flavoprotein subunit. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(7):258–65.

    PubMed  CAS  Google Scholar 

  61. Salvi M, Morrice NA, Brunati AM, Toninello A. Identification of the flavoprotein of succinate dehydrogenase and aconitase as in vitro mitochondrial substrates of Fgr tyrosine kinase. FEBS Lett. 2007;581(29):5579–85.

    PubMed  CAS  Google Scholar 

  62. Chen YR, Chen CL, Pfeiffer DR, Zweier JL. Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation. J Biol Chem. 2007;282(45):32640–54.

    PubMed  CAS  Google Scholar 

  63. Gutman M, Silman N. The steady state activity of succinate dehydrogenase in the presence of opposing effectors. II. Reductive activation of succinate dehydrogenase in presence of oxaloacetate. Mol Cell Biochem. 1975;7(3):177–85.

    PubMed  CAS  Google Scholar 

  64. Bourgeron T, Rustin P, Chretien D, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet. 1995;11(2):144–9.

    PubMed  CAS  Google Scholar 

  65. Parfait B, Chretien D, Rotig A, Marsac C, Munnich A, Rustin P. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet. 2000;106(2):236–43.

    PubMed  CAS  Google Scholar 

  66. Van Coster R, Seneca S, Smet J, et al. Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. Am J Med Genet A. 2003;120A(1):13–8.

    PubMed  Google Scholar 

  67. Horvath R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry. 2006;77(1):74–6.

    PubMed  CAS  Google Scholar 

  68. Birch-Machin MA, Taylor RW, Cochran B, Ackrell BA, Turnbull DM. Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol. 2000;48(3):330–5.

    PubMed  CAS  Google Scholar 

  69. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69(1):49–54.

    PubMed  CAS  Google Scholar 

  70. Timmers HJ, Kozupa A, Eisenhofer G, et al. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2007;92(3):779–86.

    PubMed  CAS  Google Scholar 

  71. Ricketts CJ, Forman JR, Rattenberry E, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010;31(1):41–51.

    PubMed  CAS  Google Scholar 

  72. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006;25(34):4675–82.

    PubMed  CAS  Google Scholar 

  73. Lee S, Nakamura E, Yang H, et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. 2005;8(2):155–67.

    PubMed  Google Scholar 

  74. Esteban MA, Maxwell PH. HIF, a missing link between metabolism and cancer. Nat Med. 2005;11(10):1047–8.

    PubMed  CAS  Google Scholar 

  75. Bourgeron T, Chretien D, Poggi-Bach J, et al. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J Clin Invest. 1994;93(6):2514–8.

    PubMed  CAS  Google Scholar 

  76. Hall MD, Levitt DG, Banaszak LJ. Crystal structure of Escherichia coli malate dehydrogenase. A complex of the apoenzyme and ­citrate at 1.87 A resolution. J Mol Biol. 1992;226(3):867–82.

    PubMed  CAS  Google Scholar 

  77. Gelpi JL, Dordal A, Montserrat J, Mazo A, Cortes A. Kinetic studies of the regulation of mitochondrial malate dehydrogenase by citrate. Biochem J. 1992;283(Pt 1):289–97.

    PubMed  CAS  Google Scholar 

  78. Mullinax TR, Mock JN, McEvily AJ, Harrison JH. Regulation of mitochondrial malate dehydrogenase. Evidence for an allosteric citrate-binding site. J Biol Chem. 1982;257(22):13233–9.

    PubMed  CAS  Google Scholar 

  79. Robinson Jr JB, Inman L, Sumegi B, Srere PA. Further characterization of the Krebs tricarboxylic acid cycle metabolon. J Biol Chem. 1987;262(4):1786–90.

    PubMed  CAS  Google Scholar 

  80. Wang Q, Yu L, Yu CA. Cross-talk between mitochondrial malate dehydrogenase and the cytochrome bc1 complex. J Biol Chem. 2010;285(14):10408–14.

    PubMed  CAS  Google Scholar 

  81. Lo AS, Liew CT, Ngai SM, et al. Developmental regulation and cellular distribution of human cytosolic malate dehydrogenase (MDH1). J Cell Biochem. 2005;94(4):763–73.

    PubMed  CAS  Google Scholar 

  82. Carroll J, Fearnley IM, Shannon RJ, Hirst J, Walker JE. Analysis of the subunit composition of complex I from bovine heart mitochondria. Mol Cell Proteomics. 2003;2(2):117–26.

    PubMed  CAS  Google Scholar 

  83. Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE. Bovine complex I is a complex of 45 different subunits. J Biol Chem. 2006;281(43):32724–7.

    PubMed  CAS  Google Scholar 

  84. Janssen RJ, Nijtmans LG, van den Heuvel LP, Smeitink JA. Mitochondrial complex I: structure, function and pathology. J Inherit Metab Dis. 2006;29(4):499–515.

    PubMed  CAS  Google Scholar 

  85. Hirst J, Carroll J, Fearnley IM, Shannon RJ, Walker JE. The nuclear encoded subunits of complex I from bovine heart mitochondria. Biochim Biophys Acta. 2003;1604(3):135–50.

    PubMed  CAS  Google Scholar 

  86. Vogel RO, Smeitink JA, Nijtmans LG. Human mitochondrial complex I assembly: a dynamic and versatile process. Biochim Biophys Acta. 2007;1767(10):1215–27.

    PubMed  CAS  Google Scholar 

  87. Prieur I, Lunardi J, Dupuis A. Evidence for a quinone binding site close to the interface between NUOD and NUOB subunits of Complex I. Biochim Biophys Acta. 2001;1504(2–3):173–8.

    PubMed  CAS  Google Scholar 

  88. Tocilescu MA, Fendel U, Zwicker K, Kerscher S, Brandt U. Exploring the ubiquinone binding cavity of respiratory complex I. J Biol Chem. 2007;282(40):29514–20.

    PubMed  CAS  Google Scholar 

  89. Mathiesen C, Hagerhall C. Transmembrane topology of the NuoL, M and N subunits of NADH:quinone oxidoreductase and their homologues among membrane-bound hydrogenases and bona fide antiporters. Biochim Biophys Acta. 2002;1556(2–3):121–32.

    PubMed  CAS  Google Scholar 

  90. Kussmaul L, Hirst J. The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci USA. 2006;103(20):7607–12.

    PubMed  CAS  Google Scholar 

  91. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.

    PubMed  CAS  Google Scholar 

  92. Kirby DM, Crawford M, Cleary MA, Dahl HH, Dennett X, Thorburn DR. Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder. Neurology. 1999;52(6):1255–64.

    PubMed  CAS  Google Scholar 

  93. Loeffen JL, Smeitink JA, Trijbels JM, et al. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat. 2000;15(2):123–34.

    PubMed  CAS  Google Scholar 

  94. Pitkanen S, Feigenbaum A, Laframboise R, Robinson BH. NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings. J Inherit Metab Dis. 1996;19(5):675–86.

    PubMed  CAS  Google Scholar 

  95. Bugiani M, Invernizzi F, Alberio S, et al. Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta. 2004;1659(2–3):136–47.

    PubMed  CAS  Google Scholar 

  96. Ghezzi D, Goffrini P, Uziel G, et al. SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet. 2009;41(6):654–6.

    PubMed  CAS  Google Scholar 

  97. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26(3):268–70.

    PubMed  CAS  Google Scholar 

  98. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287(5454):848–51.

    PubMed  CAS  Google Scholar 

  99. Iwata S, Lee JW, Okada K, et al. Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science. 1998;281(5373):64–71.

    PubMed  CAS  Google Scholar 

  100. Blakely EL, Mitchell AL, Fisher N, et al. A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast. FEBS J. 2005;272(14):3583–92.

    PubMed  CAS  Google Scholar 

  101. Andreu AL, Checcarelli N, Iwata S, Shanske S, DiMauro S. A missense mutation in the mitochondrial cytochrome b gene in a revisited case with histiocytoid cardiomyopathy. Pediatr Res. 2000;48(3):311–4.

    PubMed  CAS  Google Scholar 

  102. Schuelke M, Krude H, Finckh B, et al. Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation. Ann Neurol. 2002;51(3):388–92.

    PubMed  CAS  Google Scholar 

  103. Wibrand F, Ravn K, Schwartz M, Rosenberg T, Horn N, Vissing J. Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene. Ann Neurol. 2001;50(4):540–3.

    PubMed  CAS  Google Scholar 

  104. Wen JJ, Garg NJ. Mitochondrial complex III defects contribute to inefficient respiration and ATP synthesis in the myocardium of Trypanosoma cruzi-infected mice. Antioxid Redox Signal. 2010;12(1):27–37.

    PubMed  CAS  Google Scholar 

  105. Haut S, Brivet M, Touati G, et al. A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis. Hum Genet. 2003;113(2):118–22.

    PubMed  CAS  Google Scholar 

  106. Yoshikawa S, Shinzawa-Itoh K, Tsukihara T. Crystal structure of bovine heart cytochrome c oxidase at 2.8 A resolution. J Bioenerg Biomembr. 1998;30(1):7–14.

    PubMed  CAS  Google Scholar 

  107. Stiburek L, Hansikova H, Tesarova M, Cerna L, Zeman J. Biogenesis of eukaryotic cytochrome c oxidase. Physiol Res. 2006;55 Suppl 2:S27–41.

    PubMed  CAS  Google Scholar 

  108. Kadenbach B, Huttemann M, Arnold S, Lee I, Bender E. Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome c oxidase. Free Radic Biol Med. 2000;29(3–4):211–21.

    PubMed  CAS  Google Scholar 

  109. Yang WL, Iacono L, Tang WM, Chin KV. Novel function of the regulatory subunit of protein kinase A: regulation of cytochrome c oxidase activity and cytochrome c release. Biochemistry. 1998;37(40):14175–80.

    PubMed  CAS  Google Scholar 

  110. Arnold S, Goglia F, Kadenbach B. 3,5-Diiodothyronine binds to subunit Va of cytochrome-c oxidase and abolishes the allosteric inhibition of respiration by ATP. Eur J Biochem. 1998;252(2):325–30.

    PubMed  CAS  Google Scholar 

  111. Grossman LI, Lomax MI. Nuclear genes for cytochrome c oxidase. Biochim Biophys Acta. 1997;1352(2):174–92.

    PubMed  CAS  Google Scholar 

  112. Fuller SD, Darley-Usmar VM, Capaldi RA. Covalent complex between yeast cytochrome c and beef heart cytochrome c oxidase which is active in electron transfer. Biochemistry. 1981;20(24):7046–53.

    PubMed  CAS  Google Scholar 

  113. Hill BC. The reaction of the electrostatic cytochrome c-cytochrome oxidase complex with oxygen. J Biol Chem. 1991;266(4):2219–26.

    PubMed  CAS  Google Scholar 

  114. Tsukihara T, Aoyama H, Yamashita E, et al. Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 A. Science. 1995;269(5227):1069–74.

    PubMed  CAS  Google Scholar 

  115. Fetter JR, Qian J, Shapleigh J, et al. Possible proton relay pathways in cytochrome c oxidase. Proc Natl Acad Sci USA. 1995;92(5):1604–8.

    PubMed  CAS  Google Scholar 

  116. Tsukihara T, Aoyama H, Yamashita E, et al. The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A. Science. 1996;272(5265):1136–44.

    PubMed  CAS  Google Scholar 

  117. Konstantinov AA, Siletsky S, Mitchell D, Kaulen A, Gennis RB. The roles of the two proton input channels in cytochrome c oxidase from Rhodobacter sphaeroides probed by the effects of site-directed mutations on time-resolved electrogenic intraprotein proton transfer. Proc Natl Acad Sci USA. 1997;94(17):9085–90.

    PubMed  CAS  Google Scholar 

  118. Wikstrom M, Jasaitis A, Backgren C, Puustinen A, Verkhovsky MI. The role of the D- and K-pathways of proton transfer in the function of the haem-copper oxidases. Biochim Biophys Acta. 2000;1459(2–3):514–20.

    PubMed  CAS  Google Scholar 

  119. Yoshikawa S, Shinzawa-Itoh K, Nakashima R, et al. Redox-coupled crystal structural changes in bovine heart cytochrome c oxidase. Science. 1998;280(5370):1723–9.

    PubMed  CAS  Google Scholar 

  120. Riistama S, Puustinen A, Garcia-Horsman A, Iwata S, Michel H, Wikstrom M. Channelling of dioxygen into the respiratory enzyme. Biochim Biophys Acta. 1996;1275(1–2):1–4.

    PubMed  Google Scholar 

  121. Belevich I, Verkhovsky MI. Molecular mechanism of proton translocation by cytochrome c oxidase. Antioxid Redox Signal. 2008;10(1):1–29.

    PubMed  CAS  Google Scholar 

  122. Barrientos A, Barros MH, Valnot I, Rotig A, Rustin P, Tzagoloff A. Cytochrome oxidase in health and disease. Gene. 2002;286(1):53–63.

    PubMed  CAS  Google Scholar 

  123. Tiranti V, Hoertnagel K, Carrozzo R, et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet. 1998;63(6):1609–21.

    PubMed  CAS  Google Scholar 

  124. Antonicka H, Leary SC, Guercin GH, et al. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet. 2003;12(20):2693–702.

    PubMed  CAS  Google Scholar 

  125. Antonicka H, Mattman A, Carlson CG, et al. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet. 2003;72(1):101–14.

    PubMed  CAS  Google Scholar 

  126. Valnot I, Osmond S, Gigarel N, et al. Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet. 2000;67(5):1104–9.

    PubMed  CAS  Google Scholar 

  127. Papadopoulou LC, Sue CM, Davidson MM, et al. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet. 1999;23(3):333–7.

    PubMed  CAS  Google Scholar 

  128. Schagger H, Pfeiffer K. Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J. 2000;19(8):1777–83.

    PubMed  CAS  Google Scholar 

  129. Genova ML, Baracca A, Biondi A, et al. Is supercomplex organization of the respiratory chain required for optimal electron transfer activity? Biochim Biophys Acta. 2008;1777(7–8):740–6.

    PubMed  CAS  Google Scholar 

  130. Pfeiffer K, Gohil V, Stuart RA, et al. Cardiolipin stabilizes respiratory chain supercomplexes. J Biol Chem. 2003;278(52):52873–80.

    PubMed  CAS  Google Scholar 

  131. McKenzie M, Lazarou M, Thorburn DR, Ryan MT. Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol. 2006;361(3):462–9.

    PubMed  CAS  Google Scholar 

  132. Collinson IR, Runswick MJ, Buchanan SK, et al. Fo membrane domain of ATP synthase from bovine heart mitochondria: purification, subunit composition, and reconstitution with F1-ATPase. Biochemistry. 1994;33(25):7971–8.

    PubMed  CAS  Google Scholar 

  133. Stock D, Leslie AG, Walker JE. Molecular architecture of the rotary motor in ATP synthase. Science. 1999;286(5445):1700–5.

    PubMed  CAS  Google Scholar 

  134. Cox GB, Jans DA, Fimmel AL, Gibson F, Hatch L. Hypothesis. The mechanism of ATP synthase. Conformational change by rotation of the beta-subunit. Biochim Biophys Acta. 1984;768(3–4):201–8.

    PubMed  CAS  Google Scholar 

  135. Noji H, Yasuda R, Yoshida M, Kinosita Jr K. Direct observation of the rotation of F1-ATPase. Nature. 1997;386(6622):299–302.

    PubMed  CAS  Google Scholar 

  136. Minauro-Sanmiguel F, Bravo C, Garcia JJ. Cross-linking of the endogenous inhibitor protein (IF1) with rotor (gamma, epsilon) and stator (alpha) subunits of the mitochondrial ATP synthase. J Bioenerg Biomembr. 2002;34(6):433–43.

    PubMed  CAS  Google Scholar 

  137. Chen C, Ko Y, Delannoy M, Ludtke SJ, Chiu W, Pedersen PL. Mitochondrial ATP synthasome: three-dimensional structure by electron microscopy of the ATP synthase in complex formation with carriers for Pi and ADP/ATP. J Biol Chem. 2004;279(30):31761–8.

    PubMed  CAS  Google Scholar 

  138. Detke S, Elsabrouty R. Identification of a mitochondrial ATP synthase-adenine nucleotide translocator complex in Leishmania. Acta Trop. 2008;105(1):16–20.

    PubMed  CAS  Google Scholar 

  139. Houstek J, Pickova A, Vojtiskova A, Mracek T, Pecina P, Jesina P. Mitochondrial diseases and genetic defects of ATP synthase. Biochim Biophys Acta. 2006;1757(9–10):1400–5.

    PubMed  CAS  Google Scholar 

  140. Jonckheere AI, Hogeveen M, Nijtmans LG, et al. A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet. 2008;45(3):129–33.

    PubMed  CAS  Google Scholar 

  141. De Meirleir L, Seneca S, Lissens W, et al. Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet. 2004;41(2):120–4.

    PubMed  Google Scholar 

  142. Saks VA, Khuchua ZA, Vasilyeva EV, Belikova O, Kuznetsov AV. Metabolic compartmentation and substrate channelling in muscle cells. Role of coupled creatine kinases in in vivo regulation of cellular respiration—a synthesis. Mol Cell Biochem. 1994;133–134:155–92.

    PubMed  Google Scholar 

  143. Roberts J, Aubert S, Gout E, Bligny R, Douce R. Cooperation and competition between adenylate kinase, nucleoside diphosphokinase, electron transport, and ATP synthase in plant mitochondria studied by 31P-nuclear magnetic resonance. Plant Physiol. 1997;113(1):191–9.

    PubMed  CAS  Google Scholar 

  144. Dzeja PP, Vitkevicius KT, Redfield MM, Burnett JC, Terzic A. Adenylate kinase-catalyzed phosphotransfer in the myocardium: increased contribution in heart failure. Circ Res. 1999;84(10):1137–43.

    PubMed  CAS  Google Scholar 

  145. Bandlow W, Strobel G, Zoglowek C, Oechsner U, Magdolen V. Yeast adenylate kinase is active simultaneously in mitochondria and cytoplasm and is required for non-fermentative growth. Eur J Biochem. 1988;178(2):451–7.

    PubMed  CAS  Google Scholar 

  146. Schlattner U, Wallimann T. Octamers of mitochondrial creatine kinase isoenzymes differ in stability and membrane binding. J Biol Chem. 2000;275(23):17314–20.

    PubMed  CAS  Google Scholar 

  147. Schlattner U, Gehring F, Vernoux N, et al. C-terminal lysines determine phospholipid interaction of sarcomeric mitochondrial creatine kinase. J Biol Chem. 2004;279(23):24334–42.

    PubMed  CAS  Google Scholar 

  148. Dolder M, Walzel B, Speer O, Schlattner U, Wallimann T. Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation. J Biol Chem. 2003;278(20):17760–6.

    PubMed  CAS  Google Scholar 

  149. Spindler M, Niebler R, Remkes H, Horn M, Lanz T, Neubauer S. Mitochondrial creatine kinase is critically necessary for normal myocardial high-energy phosphate metabolism. Am J Physiol Heart Circ Physiol. 2002;283(2):H680–7.

    PubMed  CAS  Google Scholar 

  150. Lacombe ML, Milon L, Munier A, Mehus JG, Lambeth DO. The human Nm23/nucleoside diphosphate kinases. J Bioenerg Biomembr. 2000;32(3):247–58.

    PubMed  CAS  Google Scholar 

  151. Ray NB, Mathews CK. Nucleoside diphosphokinase: a functional link between intermediary metabolism and nucleic acid synthesis. Curr Top Cell Regul. 1992;33:343–57.

    PubMed  CAS  Google Scholar 

  152. Boissan M, Dabernat S, Peuchant E, Schlattner U, Lascu I, Lacombe ML. The mammalian Nm23/NDPK family: from metastasis control to cilia movement. Mol Cell Biochem. 2009;329(1–2):51–62.

    PubMed  CAS  Google Scholar 

  153. Lascu L, Giartosio A, Ransac S, Erent M. Quaternary structure of nucleoside diphosphate kinases. J Bioenerg Biomembr. 2000;32(3):227–36.

    PubMed  CAS  Google Scholar 

  154. Milon L, Meyer P, Chiadmi M, et al. The human nm23-H4 gene product is a mitochondrial nucleoside diphosphate kinase. J Biol Chem. 2000;275(19):14264–72.

    PubMed  CAS  Google Scholar 

  155. Adams V, Bosch W, Schlegel J, Wallimann T, Brdiczka D. Further characterization of contact sites from mitochondria of different tissues: topology of peripheral kinases. Biochim Biophys Acta. 1989;981(2):213–25.

    PubMed  CAS  Google Scholar 

  156. Tokarska-Schlattner M, Boissan M, Munier A, et al. The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration. J Biol Chem. 2008;283(38):26198–207.

    PubMed  CAS  Google Scholar 

  157. Krebs HA, Wiggins D. Phosphorylation of adenosine monophosphate in the mitochondrial matrix. Biochem J. 1978;174(1):297–301.

    PubMed  CAS  Google Scholar 

  158. Pedersen PL. Coupling of adenosine triphosphate formation in mitochondria to the formation of nucleoside triphosphates. Involvement of nucleoside diphosphokinase. J Biol Chem. 1973;248(11):3956–62.

    PubMed  CAS  Google Scholar 

  159. Van Rompay AR, Johansson M, Karlsson A. Identification of a novel human adenylate kinase. cDNA cloning, expression analysis, chromosome localization and characterization of the recombinant protein. Eur J Biochem. 1999;261(2):509–17.

    PubMed  Google Scholar 

  160. Tanabe T, Yamada M, Noma T, Kajii T, Nakazawa A. Tissue-specific and developmentally regulated expression of the genes encoding adenylate kinase isozymes. J Biochem. 1993;113(2):200–7.

    PubMed  CAS  Google Scholar 

  161. Carrasco AJ, Dzeja PP, Alekseev AE, et al. Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels. Proc Natl Acad Sci USA. 2001;98(13):7623–8.

    PubMed  CAS  Google Scholar 

  162. Zeleznikar RJ, Dzeja PP, Goldberg ND. Adenylate kinase-catalyzed phosphoryl transfer couples ATP utilization with its generation by glycolysis in intact muscle. J Biol Chem. 1995;270(13):7311–9.

    PubMed  CAS  Google Scholar 

  163. Dzeja PP, Zeleznikar RJ, Goldberg ND. Adenylate kinase: kinetic behavior in intact cells indicates it is integral to multiple cellular processes. Mol Cell Biochem. 1998;184(1–2):169–82.

    PubMed  CAS  Google Scholar 

  164. Mattaj IW, Englmeier L. Nucleocytoplasmic transport: the soluble phase. Annu Rev Biochem. 1998;67:265–306.

    PubMed  CAS  Google Scholar 

  165. Perez-Terzic C, Gacy AM, Bortolon R, et al. Directed inhibition of nuclear import in cellular hypertrophy. J Biol Chem. 2001;276(23):20566–71.

    PubMed  CAS  Google Scholar 

  166. Neumann D, Schlattner U, Wallimann T. A molecular approach to the concerted action of kinases involved in energy homoeostasis. Biochem Soc Trans. 2003;31(Pt 1):169–74.

    PubMed  CAS  Google Scholar 

  167. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J. 1992;281(Pt 1):21–40.

    PubMed  CAS  Google Scholar 

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Marín-García, J. (2013). Mechanisms of Bioenergy Production in Mitochondria. In: Mitochondria and Their Role in Cardiovascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4599-9_5

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