Mitochondrial tRNA mutations and disease

Mitochondrial (mt‐) tRNA (MTT) gene mutations are an important cause of human morbidity and are associated with a wide range of pathology, from isolated organ‐specific diseases such as myopathy or hearing loss, through to multisystem disorders with encephalopathy, gastrointestinal dysmotility, and life‐threatening cardiomyopathy. Our understanding of how MTT mutations cause disease remains poor and progress has been hampered by the complex interaction of genotype with phenotype that can result in patients who harbor the same mutation exhibiting starkly contrasting phenotypes, whereas other (genetically heterogeneous) patients manifest clinically identical syndromes. A further complexity is the highly polymorphic nature of mitochondrial DNA (mtDNA), which must temper any reflex assumptions of pathogenicity for novel MTT substitutions. Nevertheless significant progress is being made and we shall review the methods employed to identify and characterize MTT mutations as pathogenic. Also important is our understanding of the molecular processes involved and we shall discuss the data available on two of the most studied MTT mutations (m.8344A > G and m.3243A > G) as well as other potential pathogenic mechanisms. Knowledge of factors influencing the inheritance of MTT mutations, and therefore the likelihood of disease transmission, is of particular importance to female patients. At present, the factors determining transmission remain elusive, but we shall examine several possible mechanisms and discuss the evidence for each. Finally, a number of different yeast and mouse models are currently used to investigate mitochondrial disease and we will assess the importance of and difficulties associated with each model as well as the future of possible therapies for patients with mitochondrial disease. Copyright © 2010 John Wiley & Sons, Inc.

[1]  R. Wiesner,et al.  A new mechanism for mtDNA pathogenesis: impairment of post-transcriptional maturation leads to severe depletion of mitochondrial tRNASer(UCN) caused by T7512C and G7497A point mutations , 2005, Nucleic acids research.

[2]  K. Majamaa,et al.  Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. , 1998, American journal of human genetics.

[3]  F. Crick.  Codon--anticodon pairing: the wobble hypothesis. , 1966, Journal of molecular biology.

[4]  A. Harding,et al.  The mitochondrial DNA transfer RNA(Lys)A-->G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. , 1993, Brain : a journal of neurology.

[5]  E. Schon,et al.  In vitro analysis of mutations causing myoclonus epilepsy with ragged-red fibers in the mitochondrial tRNA(Lys)gene: two genotypes produce similar phenotypes , 1995, Molecular and cellular biology.

[6]  Tsutomu Suzuki,et al.  Defect in modification at the anticodon wobble nucleotide of mitochondrial tRNALys with the MERRF encephalomyopathy pathogenic mutation , 2000, FEBS letters.

[7]  Tsutomu Suzuki,et al.  [Wobble modification defect suppresses translational activity of tRNAs with MERRF and MELAS mutations]. , 2002, Nihon rinsho. Japanese journal of clinical medicine.

[8]  N. Howell,et al.  Molecular clock debate: Time dependency of molecular rate estimates for mtDNA: this is not the time for wishful thinking , 2008, Heredity.

[9]  Y. Goto,et al.  Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders. , 2009, Mitochondrion.

[10]  V. Carelli,et al.  Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction. , 2003, Trends in Genetics.

[11]  P. Mitchell,et al.  Population prevalence of the MELAS A3243G mutation. , 2007, Mitochondrion.

[12]  E. Robin,et al.  Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells , 1988, Journal of cellular physiology.

[13]  M. Carrozzi,et al.  Two novel cosegregating mutations in tRNAMet and COX III, in a patient with exercise intolerance and autoimmune polyendocrinopathy. , 2009, Mitochondrion.

[14]  P. Chinnery,et al.  Pathogenic Mitochondrial DNA Mutations Are Common in the General Population , 2008, American journal of human genetics.

[15]  D. Wallace,et al.  Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation , 1990, Cell.

[16]  A. T. Bankier,et al.  A different genetic code in human mitochondria , 1979, Nature.

[17]  F. Sanger,et al.  Sequence and organization of the human mitochondrial genome , 1981, Nature.

[18]  J. Hopfield,et al.  Experimental evidence for kinetic proofreading in the aminoacylation of tRNA by synthetase. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[19]  G. Pruijn,et al.  Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects , 2010, European Journal of Human Genetics.

[20]  Robert W. Taylor,et al.  A new mitochondrial transfer RNAPro gene mutation associated with myoclonic epilepsy with ragged-red fibers and other neurological features. , 2009, Archives of neurology.

[21]  D. Turnbull,et al.  Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. , 1997, Brain : a journal of neurology.

[22]  Takehiro Yasukawa,et al.  Modification Defect at Anticodon Wobble Nucleotide of Mitochondrial tRNAsLeu(UUR) with Pathogenic Mutations of Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes* , 2000, The Journal of Biological Chemistry.

[23]  M. Stoneking,et al.  Mitochondrial DNA and human evolution , 1987, Nature.

[24]  J. Chen,et al.  Mutations at position 7445 in the precursor of mitochondrial tRNA(Ser(UCN)) gene in three maternal Chinese pedigrees with sensorineural hearing loss. , 2008, Mitochondrion.

[25]  C. Florentz,et al.  Towards understanding human mitochondrial leucine aminoacylation identity. , 2003, Journal of molecular biology.

[26]  David C Samuels,et al.  A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes , 2008, Nature Genetics.

[27]  D. Turnbull,et al.  Pathogenic mitochondrial tRNA mutations – Which mutations are inherited and why? , 2009, Human mutation.

[28]  R Giegé,et al.  Search for characteristic structural features of mammalian mitochondrial tRNAs. , 2000, RNA.

[29]  D. Wallace.  Mitochondrial diseases in man and mouse. , 1999, Science.

[30]  M. Bolotin-Fukuhara,et al.  Yeast as a model of human mitochondrial tRNA base substitutions: investigation of the molecular basis of respiratory defects. , 2007, RNA.

[31]  R. H.J.MULLE.  THE RELATION OF RECOMBINATION TO MUTATIONAL ADVANCE , 2002 .

[32]  S. Dimauro,et al.  Mitochondrial myopathy associated with a novel mutation in mtDNA , 2007, Neuromuscular Disorders.

[33]  Douglass M. Turnbull,et al.  Does the mitochondrial genome play a role in the etiology of Alzheimer’s disease? , 2006, Human Genetics.

[34]  D. Turnbull,et al.  Annotation: Mitochondrial genotype and clinical phenotype , 1998, Journal of Inherited Metabolic Disease.

[35]  Robert W. Taylor,et al.  A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. , 2003, Journal of the American College of Cardiology.

[36]  B. Van Houten,et al.  Mitochondrial DNA repair and aging. , 2002, Mutation research.

[37]  I. Nonaka,et al.  Myoclonus epilepsy associated with ragged‐red fibers: A G‐to‐A mutation at nucleotide pair 8363 in mitochondrial tRNALys in two families , 1997, Muscle & nerve.

[38]  E. Shoubridge,et al.  Aerobic conditioning in patients with mitochondrial myopathies: Physiological, biochemical, and genetic effects , 2001, Annals of neurology.

[39]  M. Costanzo,et al.  Analysis and manipulation of yeast mitochondrial genes. , 1991, Methods in enzymology.

[40]  M. King,et al.  Post-transcriptional regulation of the steady-state levels of mitochondrial tRNAs in HeLa cells. , 1993, The Journal of biological chemistry.

[41]  C. Florentz,et al.  Effect of a mutation in the anticodon of human mitochondrial tRNAPro on its post-transcriptional modification pattern. , 1998, Nucleic acids research.

[42]  J. Enríquez,et al.  The Deafness-Associated Mitochondrial DNA Mutation at Position 7445, Which Affects tRNASer(UCN) Precursor Processing, Has Long-Range Effects on NADH Dehydrogenase Subunit ND6 Gene Expression , 1998, Molecular and Cellular Biology.

[43]  R. Wiesner,et al.  Concerted action of two novel tRNA mtDNA point mutations in chronic progressive external ophthalmoplegia. , 2008, Bioscience reports.

[44]  Takahiko Hara,et al.  The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells , 2007, Nature Genetics.

[45]  R Giegé,et al.  Universal rules and idiosyncratic features in tRNA identity. , 1998, Nucleic acids research.

[46]  M. Lehtonen,et al.  Phylogenetic network for European mtDNA. , 2001, American journal of human genetics.

[47]  M. Vannan,et al.  A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations , 2008, Science.

[48]  T Yasukawa,et al.  Wobble modification defect in tRNA disturbs codon–anticodon interaction in a mitochondrial disease , 2001, The EMBO journal.

[49]  E. Schon,et al.  Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus , 2002, Nature Genetics.

[50]  William M. Mauck,et al.  Heterologous mitochondrial DNA recombination in human cells. , 2004, Human molecular genetics.

[51]  I. Tarassov,et al.  tRNA mitochondrial import in yeast: Mapping of the import determinants in the carrier protein, the precursor of mitochondrial lysyl-tRNA synthetase. , 2010, Mitochondrion.

[52]  S. Pääbo,et al.  Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. , 2000, Human molecular genetics.

[53]  R. Lightowlers,et al.  Hungry Codons Promote Frameshifting in Human Mitochondrial Ribosomes , 2010, Science.

[54]  C. Pinkert,et al.  Mitochondria transfer into mouse ova by microinjection , 1997, Transgenic Research.

[55]  D. Wallace,et al.  Transfer of chloramphenicol‐resistant mitochondrial DNA into the chimeric mouse , 1999, Transgenic Research.

[56]  Inheritance of mitochondrial DNA recombinants in double-heteroplasmic families: potential implications for phylogenetic analysis. , 2007, American journal of human genetics.

[57]  E. Shoubridge,et al.  Sidestepping Mutational Meltdown , 2008, Science.

[58]  Tsutomu Suzuki,et al.  Acquisition of the wobble modification in mitochondrial tRNALeu(CUN) bearing the G12300A mutation suppresses the MELAS molecular defect. , 2006, Human molecular genetics.

[59]  M. King,et al.  Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene. , 2008, RNA.

[60]  L. Spremulli,et al.  Interaction of mitochondrial initiation factor 2 with mitochondrial fMet-tRNA. , 2004, Nucleic acids research.

[61]  D. Turnbull,et al.  Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. , 2004, American journal of human genetics.

[62]  N. Larsson,et al.  Molecular genetic aspects of human mitochondrial disorders. , 1995, Annual review of genetics.

[63]  S. Finnilä,et al.  Molecular epidemiology of childhood mitochondrial encephalomyopathies in a Finnish population: sequence analysis of entire mtDNA of 17 children reveals heteroplasmic mutations in tRNAArg, tRNAGlu, and tRNALeu(UUR) genes. , 2004, Pediatrics.

[64]  S. Dimauro,et al.  A mitochondrial tRNA anticodon swap associated with a muscle disease , 1993, Nature Genetics.

[65]  Y. Mechulam,et al.  Recognition of tRNAs by Methionyl-tRNA Transformylase from Mammalian Mitochondria* , 2001, The Journal of Biological Chemistry.

[66]  Robert W. Taylor,et al.  Novel mitochondrial transfer RNA(Phe) gene mutation associated with late-onset neuromuscular disease. , 2006, Archives of neurology.

[67]  M. Bolotin-Fukuhara,et al.  Mutations in yeast mt tRNAs: specific and general suppression by nuclear encoded tRNA interactors. , 2006, Gene.

[68]  D. Turnbull,et al.  MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. , 1998, Brain : a journal of neurology.

[69]  P. Sanaker,et al.  A novel mutation in the mitochondrial tRNA for tryptophan causing a late‐onset mitochondrial encephalomyopathy , 2010, Acta neurologica Scandinavica.

[70]  M. Ibba,et al.  Loss of Editing Activity during the Evolution of Mitochondrial Phenylalanyl-tRNA Synthetase* , 2005, Journal of Biological Chemistry.

[71]  P. Froguel,et al.  Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA Leu(UUR) gene , 1994, Diabetes.

[72]  D. Turnbull,et al.  Pure myopathy associated with a novel mitochondrial tRNA gene mutation , 2006, Neurology.

[73]  Robert W. Taylor,et al.  Mitochondrial DNA mutations in human disease , 2005, Nature Reviews Genetics.

[74]  K. Lawson,et al.  How is the mouse germ-cell lineage established? , 2005, Differentiation; research in biological diversity.

[75]  I. Nonaka,et al.  A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies , 1990, Nature.

[76]  M. Gambello,et al.  Exercise intolerance associated with a novel 8300t>C mutation in mitochondrial transfer RNAlys , 2006, Muscle & nerve.

[77]  C. Gissi,et al.  Nucleotide Substitution Rate of Mammalian Mitochondrial Genomes , 1999, Journal of Molecular Evolution.

[78]  F. Sanger,et al.  Different pattern of codon recognition by mammalian mitochondrial tRNAs. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Richard Giegé,et al.  The presence of modified nucleotides is required for cloverleaf folding of a human mitochondrial tRNA. , 1998, Nucleic acids research.

[80]  Stamatina Giannouli,et al.  Mitochondrial tRNA Mutations: Clinical and Functional Perturbations , 2007, RNA biology.

[81]  S. Kelley,et al.  Dimerization of a pathogenic human mitochondrial tRNA , 2002, Nature Structural Biology.

[82]  Robert W. Taylor,et al.  Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation , 2002, Nature Genetics.

[83]  S. Pääbo,et al.  Mitochondrial genome variation and the origin of modern humans , 2000, Nature.

[84]  S. Kelley,et al.  An aminoacyl-tRNA synthetase with a defunct editing site. , 2005, Biochemistry.

[85]  E. Shoubridge,et al.  The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. , 2008, Human molecular genetics.

[86]  Y. Bykhovskaya,et al.  Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. , 1998, American journal of medical genetics.

[87]  Joern Pütz,et al.  Mamit-tRNA, a database of mammalian mitochondrial tRNA primary and secondary structures. , 2007, RNA.

[88]  S. Dimauro,et al.  A functionally dominant mitochondrial DNA mutation. , 2008, Human molecular genetics.

[89]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[90]  S. Martinis,et al.  A Viable Amino Acid Editing Activity in the Leucyl-tRNA Synthetase CP1-splicing Domain Is Not Required in the Yeast Mitochondria* , 2006, Journal of Biological Chemistry.

[91]  M. King,et al.  Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. , 1989, Science.

[92]  E. Shoubridge,et al.  Gene shifting: a novel therapy for mitochondrial myopathy. , 1999, Human molecular genetics.

[93]  Robert W. Taylor,et al.  Prevalence of mitochondrial DNA disease in adults , 2008, Annals of neurology.

[94]  E. Schon,et al.  Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects , 2009, EMBO molecular medicine.

[95]  M. Deutscher,et al.  Reactions at the 3' terminus of transfer ribonucleic acid. V. Subcellular localization and evidence for a mitochondrial transfer ribonucleic acid nucleotidyltransferase. , 1972, The Journal of biological chemistry.

[96]  Shamkant B. Navathe,et al.  MITOMAP: an update on the status of the human mitochondrial genome database , 1997, Nucleic Acids Res..

[97]  N. Bresolin,et al.  In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria. , 1991, Molecular and cellular biology.

[98]  E. Shoubridge,et al.  Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA , 1996, Nature Genetics.

[99]  S. Manam,et al.  Separation and characterization of 5'- and 3'-tRNA processing nucleases from rat liver mitochondria. , 1987, The Journal of biological chemistry.

[100]  Jiong Cai,et al.  Mitochondrial tRNASer(UCN) gene is the hot spot for mutations associated with aminoglycoside-induced and non-syndromic hearing loss. , 2007, Biochemical and biophysical research communications.

[101]  D. Dressman,et al.  Heteroplasmic mitochondrial DNA mutations in normal and tumor cells , 2010, Nature.

[102]  G. Cortopassi,et al.  Mitochondrial defects and hearing loss , 2000, Cellular and Molecular Life Sciences CMLS.

[103]  K Watanabe,et al.  Mammalian Mitochondrial Methionyl-tRNA Transformylase from Bovine Liver , 1998, The Journal of Biological Chemistry.

[104]  Robert W. Taylor,et al.  Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation , 2008, Nucleic acids research.

[105]  Takashi Ohtsuki,et al.  A unique serine-specific elongation factor Tu found in nematode mitochondria , 2003, Nature Structural Biology.

[106]  E. Schon,et al.  Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy , 2002, Annals of neurology.

[107]  E. Shoubridge,et al.  The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes , 2008, Nature Genetics.

[108]  B. Spiegelman,et al.  Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. , 2008, Cell metabolism.

[109]  A. Tessa,et al.  Identification of a new mtDNA mutation (14724G>A) associated with mitochondrial leukoencephalopathy. , 2007, Biochemical and biophysical research communications.

[110]  N. Pace,et al.  Ribonuclease P: unity and diversity in a tRNA processing ribozyme. , 1998, Annual review of biochemistry.

[111]  A. Pandya,et al.  Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. , 1999, American journal of human genetics.

[112]  J. Elson,et al.  Strong Purifying Selection in Transmission of Mammalian Mitochondrial DNA , 2008, PLoS biology.

[113]  Robert W. Taylor,et al.  Assigning pathogenicity to mitochondrial tRNA mutations: when "definitely maybe" is not good enough. , 2004, Trends in genetics : TIG.

[114]  Y. Mechulam,et al.  Aminoacyl-tRNA Synthetases: Occurrence, Structure, and Function , 1995 .

[115]  C. Florentz,et al.  Human mitochondrial tRNAs in health and disease , 2003, Cellular and Molecular Life Sciences CMLS.

[116]  S Thirup,et al.  The crystal structure of Cys-tRNACys-EF-Tu-GDPNP reveals general and specific features in the ternary complex and in tRNA. , 1999, Structure.

[117]  D. Turnbull,et al.  Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. , 1997, Trends in genetics : TIG.

[118]  D. Gatti,et al.  Mitochondrial aminoacyl-tRNA synthetases. , 1990, Progress in nucleic acid research and molecular biology.

[119]  Laura C. Greaves,et al.  Mitochondrial DNA mutations in human disease , 2006, IUBMB life.

[120]  M. Bolotin-Fukuhara,et al.  Reintroduction of a characterized Mit tRNA glycine mutation into yeast mitochondria provides a new tool for the study of human neurodegenerative diseases , 2001, Yeast.

[121]  M. Bolotin-Fukuhara,et al.  The yeast counterparts of human ‘MELAS’ mutations cause mitochondrial dysfunction that can be rescued by overexpression of the mitochondrial translation factor EF‐Tu , 2003, EMBO reports.

[122]  Alfredo Coppa,et al.  The Role of Selection in the Evolution of Human Mitochondrial Genomes , 2006, Genetics.

[123]  E. Schon,et al.  Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. , 1992, Molecular and cellular biology.

[124]  H. Yonekawa,et al.  New Evidence Confirms That the Mitochondrial Bottleneck Is Generated without Reduction of Mitochondrial DNA Content in Early Primordial Germ Cells of Mice , 2009, PLoS genetics.

[125]  M. Neiman,et al.  The causes of mutation accumulation in mitochondrial genomes , 2009, Proceedings of the Royal Society B: Biological Sciences.

[126]  M. Bolotin-Fukuhara,et al.  Can yeast be used to study mitochondrial diseases? Biolistic tRNA mutants for the analysis of mechanisms and suppressors. , 2009, Mitochondrion.

[127]  W. Hauswirth,et al.  Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[128]  E. Schon,et al.  Fine mapping of mitochondrial RNAs derived from the mtDNA region containing a point mutation associated with MELAS. , 1993, Nucleic acids research.

[129]  N. Martin.  Organellar tRNAs: Biosynthesis and Function , 1995 .

[130]  J. Enríquez,et al.  MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination , 1995, Nature Genetics.

[131]  T. Fox,et al.  Suppression of mutations in mitochondrial DNA by tRNAs imported from the cytoplasm. , 2000, Science.

[132]  Robert W. Taylor,et al.  Sporadic myopathy and exercise intolerance associated with the mitochondrial 8328G>A tRNALys mutation , 2007, Journal of Neurology.

[133]  T. Kunkel,et al.  Fidelity of mammalian DNA polymerases. , 1981, Science.

[134]  Julio Montoya,et al.  tRNA punctuation model of RNA processing in human mitochondria , 1981, Nature.

[135]  C O Lovejoy.  Models of human evolution. , 1982, Science.

[136]  M. Zeviani,et al.  Mitochondrial disorders. , 2004, Brain : a journal of neurology.

[137]  P. Chinnery,et al.  Is selection required for the accumulation of somatic mitochondrial DNA mutations in post-mitotic cells? , 2006, Neuromuscular Disorders.

[138]  J. Hayashi,et al.  [Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes]. , 2001, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[139]  J. Taanman,et al.  The mitochondrial genome: structure, transcription, translation and replication. , 1999, Biochimica et biophysica acta.

[140]  S. Seneca,et al.  Two novel mitochondrial DNA mutations in muscle tissue of a patient with limb-girdle myopathy. , 2007, Archives of neurology.

[141]  J. Elson,et al.  Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease , 2008, Nature Reviews Genetics.

[142]  S. Martinis,et al.  CP1-dependent partitioning of pretransfer and posttransfer editing in leucyl-tRNA synthetase , 2008, Proceedings of the National Academy of Sciences.

[143]  I. Nonaka,et al.  MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[144]  H. Jacobs,et al.  A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness , 1994, Human mutation.