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Pathogenic Implications of Human Mitochondrial Aminoacyl-tRNA Synthetases

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Aminoacyl-tRNA Synthetases in Biology and Medicine

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 344))

Abstract

Mitochondria are considered as the powerhouse of eukaryotic cells. They host several central metabolic processes fueling the oxidative phosphorylation pathway (OXPHOS) that produces ATP from its precursors ADP and inorganic phosphate Pi (PPi). The respiratory chain complexes responsible for the OXPHOS pathway are formed from complementary sets of protein subunits encoded by the nuclear genome and the mitochondrial genome, respectively. The expression of the mitochondrial genome requires a specific and fully active translation machinery from which aminoacyl-tRNA synthetases (aaRSs) are key actors. Whilst the macromolecules involved in mammalian mitochondrial translation have been under investigation for many years, there has been an explosion of interest in human mitochondrial aaRSs (mt-aaRSs) since the discovery of a large (and growing) number of mutations in these genes that are linked to a variety of neurodegenerative disorders. Herein we will review the present knowledge on mt-aaRSs in terms of their biogenesis, their connection to mitochondrial respiration, i.e., the respiratory chain (RC) complexes, and to the mitochondrial translation machinery. The pathology-related mutations detected so far are described, with special attention given to their impact on mt-aaRSs biogenesis, functioning, and/or subsequent activities. The collected data to date shed light on the diverse routes that are linking primary molecular possible impact of a mutation to its phenotypic expression. It is envisioned that a variety of mechanisms, inside and outside the translation machinery, would play a role on the heterogeneous manifestations of mitochondrial disorders.

Note: Rigorously, amino acid conversion of a given mutation should be preceded by the letter “p.” to indicate that the protein level is considered. For example, the 172C > G nucleotide change engenders the p.R58G mutation in DARS2 (referencing the gene) or mt-AspRS (referencing the protein). For sake of simplicity, the “p.” is omitted throughout the chapter.

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Abbreviations

AaRS:

Aminoacyl-tRNA synthetase (specificity is indicated by the name of the amino acid (abbreviated in a three-letter code) transferred to the cognate tRNA. As an example, AspRS stands for aspartyl-tRNA synthetase)

mt:

Mitochondrial

MTS:

Mitochondrial targeting sequence

RC:

Respiratory chain

References

  1. Scheffler IE (2001) A century of mitochondrial research: achievements and perspectives. Mitochondrion 1:3–31

    CAS  Google Scholar 

  2. Anderson S, Bankier AT, Barrell BG et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465

    CAS  Google Scholar 

  3. Ojala D, Montoya J, Attardi G (1981) tRNA punctuation model of RNA processing in human mitochondria. Nature 290:470–474

    CAS  Google Scholar 

  4. Christian BE, Spremulli LL (2012) Mechanism of protein biosynthesis in mammalian mitochondria. Biochim Biophys Acta 1819:1035–1054

    CAS  Google Scholar 

  5. Florentz C, Sohm B, Tryoen-Tóth P et al (2003) Human mitochondrial tRNAs in health and disease. Cell Mol Life Sci 60:1356–1375

    CAS  Google Scholar 

  6. Suzuki T, Nagao A, Suzuki T (2011) Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu Rev Genet 45:299–329

    CAS  Google Scholar 

  7. Watanabe K (2010) Unique features of animal mitochondrial translation systems. The non-universal genetic code, unusual features of the translational apparatus and their relevance to human mitochondrial diseases. Proc Jpn Acad Ser B Phys Biol Sci 86:11–39

    CAS  Google Scholar 

  8. Bonnefond L, Fender A, Rudinger-Thirion J et al (2005) Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry 44:4805–4816

    CAS  Google Scholar 

  9. Sissler M, Pütz J, Fasiolo F, Florentz C (2005) Mitochondrial aminoacyl-tRNA synthetases. In: Ibba M, Francklyn C, Cusack S (eds) Aminoacyl-tRNA synthetases. Landes Biosciences, Georgetown, pp 271–284

    Google Scholar 

  10. Ylikallio E, Suomalainen A (2012) Mechanisms of mitochondrial diseases. Ann Med 44:41–59

    CAS  Google Scholar 

  11. Shoffner JM, Lott MT, Lezza AM et al (1990) Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61:931–937

    CAS  Google Scholar 

  12. Goto Y, Nonaka I, Horai S (1990) A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651–653

    CAS  Google Scholar 

  13. Dimauro S, Davidzon G (2005) Mitochondrial DNA and disease. Ann Med 37:222–232

    CAS  Google Scholar 

  14. Diaz F (2010) Cytochrome c oxidase deficiency: patients and animal models. Biochim Biophys Acta 1802:100–110

    CAS  Google Scholar 

  15. Stumpf JD, Copeland WC (2011) Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations. Cell Mol Life Sci 68:219–233

    CAS  Google Scholar 

  16. Scheper GD, Van der Knaap MS, Proud CG (2007) Translation matters: protein synthesis defects in inherited disease. Nat Rev Genet 8:711–723

    Google Scholar 

  17. Konovalova S, Tyynismaa H (2013) Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab 108:206–211

    CAS  Google Scholar 

  18. Reeve AK, Krishnan KJ, Turnbull D (2009) Mitochondrial DNA mutations in disease, aging, and neurodegeneration. Ann N Y Acad Sci 1147:21–29

    Google Scholar 

  19. Wallace DC (2010) Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 51:440–450

    CAS  Google Scholar 

  20. McFarland R, Elson JL, Taylor RW et al (2004) Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough. Trends Genet 20:591–596

    CAS  Google Scholar 

  21. Zeviani M, Di Donato S (2004) Mitochondrial disorders. Brain 127:2153–2172

    Google Scholar 

  22. Smits P, Smeitink J, Van den Heuvel L (2010) Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010:737385

    Google Scholar 

  23. Fernández-Silva P, Acín-Pérez R, Fernández-Vizarra E et al (2007) In vivo and in organello analyses of mitochondrial translation. Methods Cell Biol 80:571–588

    Google Scholar 

  24. DiMauro S, Hirano M (2003) Mitochondrial DNA deletion syndromes. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adm MP (eds) GeneReviews, Seattle

    Google Scholar 

  25. Kunz WS, Kudin A, Vielhaber S et al (2000) Flux control of cytochrome c oxidase in human skeletal muscle. J Biol Chem 275:27741–27745

    CAS  Google Scholar 

  26. Munnich A, Rustin P (2001) Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet 106:4–17

    CAS  Google Scholar 

  27. Barrientos A (2002) In vivo and in organello assessment of OXPHOS activities. Methods 26:307–316

    CAS  Google Scholar 

  28. Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435:297–312

    CAS  Google Scholar 

  29. Chance B, Williams GR (1955) A simple and rapid assay of oxidative phosphorylation. Nature 175:1120–1121

    CAS  Google Scholar 

  30. N’Guessan B, Zoll J, Ribera F et al (2004) Evaluation of quantitative and qualitative aspects of mitochondrial function in human skeletal and cardiac muscles. Mol Cell Biochem 256–257:267–280

    Google Scholar 

  31. Veksler VI, Kuznetsov AV, Sharov VG et al (1987) Mitochondrial respiratory parameters in cardiac tissue: a novel method of assessment by using saponin-skinned fibers. Biochim Biophys Acta 892:191–196

    CAS  Google Scholar 

  32. Letellier T, Malgat M, Coquet M et al (1992) Mitochondrial myopathy studies on permeabilized muscle fibers. Pediatr Res 32:17–22

    CAS  Google Scholar 

  33. Bouitbir J, Charles A-L, Echaniz-Laguna A et al (2012) Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a “mitohormesis” mechanism involving reactive oxygen species and PGC-1. Eur Heart J 33:1397–1407

    CAS  Google Scholar 

  34. Nijtmans LG, Henderson NS, Holt IJ (2002) Blue native electrophoresis to study mitochondrial and other protein complexes. Methods 26:327–334

    CAS  Google Scholar 

  35. Brown WM, George M Jr, Wilson AC (1979) Rapid evolution of animal mitochondrial DNA. Proc Natl Acad Sci USA 76:1967–1971

    CAS  Google Scholar 

  36. Castellana S, Vicario S, Saccone C (2011) Evolutionary patterns of the mitochondrial genome in Metazoa: exploring the role of mutation and selection in mitochondrial protein coding genes. Genome Biol Evol 3:1067–1079

    CAS  Google Scholar 

  37. Giegé R, Jühling F, Pütz J et al (2012) Structure of transfer RNAs: similarity and variability. Wiley Interdiscip Rev RNA 3:37–61

    Google Scholar 

  38. Helm M, Brulé H, Friede D et al (2000) Search for characteristic structural features of mammalian mitochondrial tRNAs. RNA 6:1356–1379

    CAS  Google Scholar 

  39. Mudge SJ, Williams JH, Eyre HJ et al (1998) Complex organisation of the 5′-end of the human glycine tRNA synthetase gene. Gene 209:45–50

    CAS  Google Scholar 

  40. Shiba K, Schimmel P, Motegi H, Noda T (1994) Human glycyl-tRNA synthetase. Wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation. J Biol Chem 269:30049–30055

    CAS  Google Scholar 

  41. Tolkunova E, Park H, Xia J et al (2000) The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript. J Biol Chem 275:35063–35069

    CAS  Google Scholar 

  42. Rinehart J, Krett B, Rubio MA et al (2005) Saccharomyces cerevisiae imports the cytosolic pathway for Gln-tRNA synthesis into the mitochondrion. Genes Dev 19:583–592

    CAS  Google Scholar 

  43. Ibba M, Soll D (2000) Aminoacyl-tRNA synthesis. Annu Rev Biochem 69:617–650

    CAS  Google Scholar 

  44. Pujol C, Bailly M, Kern D et al (2008) Dual-targeted tRNA-dependent amidotransferase ensures both mitochondrial and chloroplastic Gln-tRNAGln synthesis in plants. Proc Natl Acad Sci USA 105:6481–6485

    CAS  Google Scholar 

  45. Schön A, Kannangara CG, Gough S, Söll D (1988) Protein biosynthesis in organelles requires misaminoacylation of tRNA. Nature 331:187–190

    Google Scholar 

  46. Frechin M, Duchêne A-M, Becker HD (2009) Translating organellar glutamine codons: a case by case scenario? RNA Biol 6:31–34

    CAS  Google Scholar 

  47. Nagao A, Suzuki T, Katoh T et al (2009) Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. Proc Natl Acad Sci USA 106:16209–16214

    CAS  Google Scholar 

  48. Frechin M, Senger B, Brayé M et al (2009) Yeast mitochondrial Gln-tRNA(Gln) is generated by a GatFAB-mediated transamidation pathway involving Arc1p-controlled subcellular sorting of cytosolic GluRS. Genes Dev 23:1119–1130

    CAS  Google Scholar 

  49. Alfonzo JD, Söll D (2009) Mitochondrial tRNA import–the challenge to understand has just begun. Biol Chem 390:717–722

    CAS  Google Scholar 

  50. Gray MW, Burger G, Lang BF (1999) Mitochondrial evolution. Science 283:1476–1481

    CAS  Google Scholar 

  51. Brindefalk B, Viklund J, Larsson D et al (2007) Origin and evolution of the mitochondrial aminoacyl-tRNA synthetases. Mol Biol Evol 24:743–756

    CAS  Google Scholar 

  52. Pfanner N (2000) Protein sorting: recognizing mitochondrial presequences. Curr Biol 10:R412–R415

    CAS  Google Scholar 

  53. Baker MJ, Frazier AE, Gulbis JM, Ryan MT (2007) Mitochondrial protein-import machinery: correlating structure with function. Trends Cell Biol 17:456–464

    CAS  Google Scholar 

  54. Becker T, Böttinger L, Pfanner N (2012) Mitochondrial protein import: from transport pathways to an integrated network. Trends Biochem Sci 37:85–91

    CAS  Google Scholar 

  55. Bolender N, Sickmann A, Wagner R et al (2008) Multiple pathways for sorting mitochondrial precursor proteins. EMBO Rep 9:42–49

    CAS  Google Scholar 

  56. Gakh O, Cavadini P, Isaya G (2002) Mitochondrial processing peptidases. Biochim Biophys Acta 1592:63–77

    CAS  Google Scholar 

  57. Van der Laan M, Hutu DP, Rehling P (2010) On the mechanism of preprotein import by the mitochondrial presequence translocase. Biochim Biophys Acta 1803:732–739

    Google Scholar 

  58. Neupert W, Herrmann JM (2007) Translocation of proteins into mitochondria. Annu Rev Biochem 76:723–749

    CAS  Google Scholar 

  59. Schmidt O, Pfanner N, Meisinger C (2010) Mitochondrial protein import: from proteomics to functional mechanisms. Nat Rev Mol Cell Biol 11:655–667

    CAS  Google Scholar 

  60. Vögtle F-N, Wortelkamp S, Zahedi RP et al (2009) Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability. Cell 139:428–439

    Google Scholar 

  61. Varshavsky A (2011) The N-end rule pathway and regulation by proteolysis. Protein Sci 20(8):1298–1345

    CAS  Google Scholar 

  62. Sissler M, Lorber B, Messmer M et al (2008) Handling mammalian mitochondrial tRNAs and aminoacyl-tRNA synthetases for functional and structural characterization. Methods 44:176–189

    CAS  Google Scholar 

  63. Bullard JM, Cai YC, Spremulli LL (2000) Expression and characterization of the human mitochondrial leucyl-tRNA synthetase. Biochim Biophys Acta 1490:245–258

    CAS  Google Scholar 

  64. Yao Y-N, Wang L, Wu X-F, Wang E-D (2003) Human mitochondrial leucyl-tRNA synthetase with high activity produced from Escherichia coli. Protein Expr Purif 30:112–116

    CAS  Google Scholar 

  65. Gaudry A, Lorber B, Neuenfeldt A et al (2012) Re-designed N-terminus enhances expression, solubility and crystallizability of mitochondrial protein. Protein Eng Des Sel 25:473–481

    CAS  Google Scholar 

  66. Neuenfeldt A, Lorber B, Ennifar E et al (2012) Thermodynamic properties distinguish human mitochondrial aspartyl-tRNA synthetase from bacterial homolog with same 3D architecture. Nucleic Acids Res 41:2698–2708

    Google Scholar 

  67. Cusack S, Berthet-Colominas C, Härtlein M et al (1990) A second class of synthetase structure revealed by X-ray analysis of Escherichia coli seryl-tRNA synthetase at 2.5Å. Nature 347:249–255

    CAS  Google Scholar 

  68. Eriani G, Delarue M, Poch O et al (1990) Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifs. Nature 347:203–206

    CAS  Google Scholar 

  69. Guo M, Schimmel P, Yang X-L (2010) Functional expansion of human tRNA synthetases achieved by structural inventions. FEBS Lett 584:434–442

    CAS  Google Scholar 

  70. Bullard JM, Cai YC, Demeler B, Spremulli LL (1999) Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase. J Mol Biol 288:567–577

    CAS  Google Scholar 

  71. Sanni A, Walter P, Boulanger Y et al (1991) Evolution of aminoacyl-tRNA synthetase quaternary structure and activity: Saccharomyces cerevisiae mitochondrial phenylalanyl-tRNA synthetase. Proc Natl Acad Sci USA 88:8387–8391

    CAS  Google Scholar 

  72. Klipcan L, Moor N, Finarov I et al (2012) Crystal structure of human mitochondrial PheRS complexed with tRNAPhe in the active “open” state. J Mol Biol 415:527–537

    CAS  Google Scholar 

  73. Kaiser E, Hu B, Becher S et al (1994) The human EPRS locus (formerly the QARS locus): a gene encoding a class I and a class II aminoacyl-tRNA synthetase. Genomics 19:280–290

    CAS  Google Scholar 

  74. Bhat TN, Blow DM, Brick P, Nyborg J (1982) Tyrosyl-tRNA synthetase forms a mononucleotide-binding fold. J Mol Biol 158:699–709

    CAS  Google Scholar 

  75. Chimnaronk S, Gravers Jeppesen M, Suzuki T et al (2005) Dual-mode recognition of noncanonical tRNAsSer by seryl-tRNA synthetase in mammalian mitochondria. EMBO J 24:3369–3379

    CAS  Google Scholar 

  76. Bonnefond L, Frugier M, Touzé E et al (2007) Crystal structure of human mitochondrial tyrosyl-tRNA synthetase reveals common and idiosyncratic features. Structure 15:1505–1516

    CAS  Google Scholar 

  77. Klipcan L, Levin I, Kessler N et al (2008) The tRNA-induced conformational activation of human mitochondrial phenylalanyl-tRNA synthetase. Structure 16:1095–1104

    CAS  Google Scholar 

  78. Fender A, Sauter C, Messmer M et al (2006) Loss of a primordial identity element for a mammalian mitochondrial aminoacylation system. J Biol Chem 281:15980–15986

    CAS  Google Scholar 

  79. Messmer M, Blais SP, Balg C et al (2009) Peculiar inhibition of human mitochondrial aspartyl-tRNA synthetase by adenylate analogs. Biochimie 91:596–603

    CAS  Google Scholar 

  80. Fender A, Gaudry A, Jühling F et al (2012) Adaptation of aminoacylation identity rules to mammalian mitochondria. Biochimie 94:1090–1097

    CAS  Google Scholar 

  81. Kumazawa Y, Himeno H, Miura K, Watanabe K (1991) Unilateral aminoacylation specificity between bovine mitochondria and eubacteria. J Biochem 109:421–427

    CAS  Google Scholar 

  82. Scheper GC, Van der Klok T, Van Andel RJ et al (2007) Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39:534–539

    Google Scholar 

  83. Isohanni P, Linnankivi T, Buzkova J et al (2010) DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis. J Med Genet 47:66–70

    CAS  Google Scholar 

  84. Labauge P, Dorboz I, Eymard-Pierre E et al (2011) Clinically asymptomatic adult patient with extensive LBSL MRI pattern and DARS2 mutations. J Neurol 258:335–337

    Google Scholar 

  85. Lin J, Chiconelli Faria E, Da Rocha AJ et al (2010) Leukoencephalopathy with brainstem and spinal cord involvement and normal lactate: a new mutation in the DARS2 gene. J Child Neurol 25:1425–1428

    CAS  Google Scholar 

  86. Namavar Y, Barth PG, Kasher PR et al (2011) Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 134:143–156

    Google Scholar 

  87. Rankin J, Brown R, Dobyns WB et al (2010) Pontocerebellar hypoplasia type 6: a British case with PEHO-like features. Am J Med Genet A 152A:2079–2084

    CAS  Google Scholar 

  88. Sharma S, Sankhyan N, Kumar A et al (2011) Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case without elevated white matter lactate. J Child Neurol 26:773–776

    Google Scholar 

  89. Steenweg ME, Ghezzi D, Haack T et al (2012) Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL' caused by EARS2 mutations. Brain 135:1387–1394

    Google Scholar 

  90. Pierce SB, Chisholm KM, Lynch ED et al (2011) Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA 108:6543–6548

    CAS  Google Scholar 

  91. Cassandrini D, Cilio MR, Bianchi M et al (2012) Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients. J Inherit Metab Dis 36:43–53

    Google Scholar 

  92. Glamuzina E, Brown R, Hogarth K et al (2012) Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. J Inherit Metab Dis 35:459–467

    Google Scholar 

  93. Antonellis A, Green ED (2008) The role of aminoacyl-tRNA synthetases in genetic diseases. Annu Rev Genomics Hum Genet 9:87–107

    CAS  Google Scholar 

  94. Miyake N, Yamashita S, Kurosawa K et al (2011) A novel homozygous mutation of DARS2 may cause a severe LBSL variant. Clin Genet 80:293–296

    CAS  Google Scholar 

  95. Synofzik M, Schicks J, Lindig T et al (2011) Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation. J Med Genet 48:713–715

    CAS  Google Scholar 

  96. Van Berge L, Dooves S, Van Berkel CG et al (2012) Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA. Biochem J 441:955–962

    Google Scholar 

  97. Riley LG, Cooper S, Hickey P et al (2010) Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia–MLASA syndrome. Am J Hum Genet 87:52–59

    CAS  Google Scholar 

  98. Bayat V, Thiffault I, Jaiswal M et al (2012) Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLoS Biol 10:e1001288

    CAS  Google Scholar 

  99. Mierzewska H, Van der Knaap MS, Scheper GC et al (2011) Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation in the first Polish patient. Brain Dev 33:713–717

    Google Scholar 

  100. Yamashita S, Miyake N, Matsumoto N et al (2012) Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2. Brain Dev 35:312–316

    Google Scholar 

  101. Edvardson S, Shaag A, Kolesnikova O et al (2007) Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 81:857–862

    CAS  Google Scholar 

  102. Van Berge L, Kevenaar J, Polder E et al (2012) Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways. Biochem J 450:345–350

    Google Scholar 

  103. Messmer M, Florentz C, Schwenzer H et al (2011) A human pathology-related mutation prevents import of an aminoacyl-tRNA synthetase into mitochondria. Biochem J 433:441–446

    CAS  Google Scholar 

  104. Elo JM, Yadavalli SS, Euro L et al (2012) Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum Mol Genet 21:4521–4529

    CAS  Google Scholar 

  105. Chang GG, Pan F, Yeh C, Huang TM (1983) Colorimetric assay for aminoacyl-tRNA synthetases. Anal Biochem 130:171–176

    CAS  Google Scholar 

  106. Sissler M, Helm M, Frugier M et al (2004) Aminoacylation properties of pathology-related human mitochondrial tRNA(Lys) variants. RNA 10:841–853

    CAS  Google Scholar 

  107. Köhrer C, Rajbhandary UL (2008) The many applications of acid urea polyacrylamide gel electrophoresis to studies of tRNAs and aminoacyl-tRNA synthetases. Methods 44:129–138

    Google Scholar 

  108. Belostotsky R, Ben-Shalom E, Rinat C et al (2011) Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 88:193–200

    CAS  Google Scholar 

  109. Sasarman F, Nishimura T, Thiffault I, Shoubridge EA (2012) A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia. Hum Mutat 33:1201–1206

    CAS  Google Scholar 

  110. Götz A, Tyynismaa H, Euro L et al (2011) Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet 88:635–642

    Google Scholar 

  111. Sasarman F, Karpati G, Shoubridge EA (2002) Nuclear genetic control of mitochondrial translation in skeletal muscle revealed in patients with mitochondrial myopathy. Hum Mol Genet 11:1669–1681

    CAS  Google Scholar 

  112. Orcesi S, La Piana R, Uggetti C et al (2011) Spinal cord calcification in an early-onset progressive leukoencephalopathy. J Child Neurol 26:876–880

    Google Scholar 

  113. Rötig A (2011) Human diseases with impaired mitochondrial protein synthesis. Biochim Biophys Acta 1807:1198–1205

    Google Scholar 

  114. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488

    CAS  Google Scholar 

  115. Yarham JW, Elson JL, Blakely EL et al (2010) Mitochondrial tRNA mutations and disease. Wiley Interdiscip Rev RNA 1:304–324

    CAS  Google Scholar 

  116. Levinger L, Mörl M, Florentz C (2004) Mitochondrial tRNA 3′ end metabolism and human disease. Nucleic Acids Res 32:5430–5441

    CAS  Google Scholar 

  117. Wittenhagen LM, Kelley SO (2003) Impact of disease-related mitochondrial mutations on tRNA structure and function. Trends Biochem Sci 28:605–611

    CAS  Google Scholar 

  118. Jacobs HT, Holt IJ (2000) The np 3243 MELAS mutation: damned if you aminoacylate, damned if you don’t. Hum Mol Genet 9:463–465

    CAS  Google Scholar 

  119. Guo M, Schimmel P (2013) Essential nontranslational functions of tRNA synthetases. Nat Chem Biol 9:145–153

    Google Scholar 

  120. Wakasugi K, Slike BM, Hood J et al (2002) Induction of angiogenesis by a fragment of human tyrosyl-tRNA synthetase. J Biol Chem 277:20124–20126

    CAS  Google Scholar 

  121. Wakasugi K, Slike BM, Hood J et al (2002) A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. Proc Natl Acad Sci USA 99:173–177

    CAS  Google Scholar 

  122. Kawahara A, Stainier DYR (2009) Noncanonical activity of seryl-transfer RNA synthetase and vascular development. Trends Cardiovasc Med 19:179–182

    CAS  Google Scholar 

  123. Park SG, Schimmel P, Kim S (2008) Aminoacyl tRNA synthetases and their connections to disease. Proc Natl Acad Sci 105:11043–11049

    CAS  Google Scholar 

  124. Seburn KL, Nangle LA, Cox GA et al (2006) An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron 51:715–726

    CAS  Google Scholar 

  125. Storkebaum E, Leitão-Gonçalves R, Godenschwege T et al (2009) Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy. Proc Natl Acad Sci USA 106:11782–11787

    CAS  Google Scholar 

  126. Hausmann CD, Ibba M (2008) Aminoacyl-tRNA synthetase complexes: molecular multitasking revealed. FEMS Microbiol Rev 32:705–721

    CAS  Google Scholar 

  127. Han JM, Lee MJ, Park SG et al (2006) Hierarchical network between the components of the multi-tRNA synthetase complex: implications for complex formation. J Biol Chem 281:38663–38667

    CAS  Google Scholar 

  128. Kaminska M, Havrylenko S, Decottignies P et al (2009) Dissection of the structural organization of the aminoacyl-tRNA synthetase complex. J Biol Chem 284:6053–6060

    CAS  Google Scholar 

  129. Ray PS, Arif A, Fox PL (2007) Macromolecular complexes as depots for releasable regulatory proteins. Trends Biochem Sci 32:158–164

    CAS  Google Scholar 

  130. Guo M, Yang X-L, Schimmel P (2010) New functions of aminoacyl-tRNA synthetases beyond translation. Nat Rev Mol Cell Biol 11:668–674

    CAS  Google Scholar 

  131. Uluc K, Baskan O, Yildirim KA et al (2008) Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case with distinct MRI findings. J Neurol Sci 273:118–122

    Google Scholar 

  132. Tzoulis C, Tran GT, Gjerde IO et al (2012) Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene. J Neurol 259:292–296

    Google Scholar 

  133. Talim B, Pyle A, Griffin H et al (2013) Multisystem fatal infantile disease caused by a novel homozygous EARS2 mutation. Brain 136:e228

    Google Scholar 

  134. Shamseldin HE, Alshammari M, Al-Sheddi T et al (2012) Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. J Med Genet 49:234–241

    Google Scholar 

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Acknowledgements

We thank Redmond Smyth for many stylistic improvements of the manuscript. Our work is supported by Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UdS), and the French National Program “Investissement d’Avenir” (Labex MitCross), administered by the “Agence National de la Recherche,” and referenced ANR-10-IDEX-002-02. The ADIRAL association is acknowledged. HS was supported by Région Alsace, Université de Strasbourg, Association Française contre les Mytopathies (AFM) and Fondation des Treilles.

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  1. Architecture et Réactivité de l’ARN, CNRS, Université de Strasbourg, IBMC, 15 rue René Descartes, 67084, Strasbourg Cedex, France

    Hagen Schwenzer, Catherine Florentz & Marie Sissler

  2. Faculté de médecine, EA 3072, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France

    Joffrey Zoll

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  1. Hagen Schwenzer
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  2. Joffrey Zoll
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  3. Catherine Florentz
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  4. Marie Sissler
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Correspondence to Marie Sissler .

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  1. Department of Molecular Medicine and Biopharmaceutical Sciences, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Korea, Republic of (South Korea)

    Sunghoon Kim

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Schwenzer, H., Zoll, J., Florentz, C., Sissler, M. (2013). Pathogenic Implications of Human Mitochondrial Aminoacyl-tRNA Synthetases. In: Kim, S. (eds) Aminoacyl-tRNA Synthetases in Biology and Medicine. Topics in Current Chemistry, vol 344. Springer, Dordrecht. https://doi.org/10.1007/128_2013_457

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