Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs

Mitochondrial DNA mutations that cause mitochondrial dysfunction are responsible for a wide spectrum of human diseases, referred to as mitochondrial diseases. Pathogenic point mutations are found frequently in genes encoding mitochondrial (mt) tRNAs, indicating that impaired functioning of mutant mt tRNAs is the primary cause of mitochondrial dysfunction. Our previous studies revealed the absence of posttranscriptional taurine modification at the anticodon wobble uridine in mutant mt tRNAs isolated from cells derived from patients with two major classes of mitochondrial diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes) and MERRF (myoclonus epilepsy associated with ragged red fibers). Defective taurine modification of the mutant mt tRNAs results in a deficiency in protein synthesis as the cognate codons of the mutant mt tRNA cannot be decoded. These findings represent the first evidence of a molecular pathogenesis caused by an RNA modification disorder. WIREs RNA 2011 2 376–386 DOI: 10.1002/wrna.65

[1]  Y. Ohya,et al.  Mitochondria-specific RNA-modifying Enzymes Responsible for the Biosynthesis of the Wobble Base in Mitochondrial tRNAs , 2005, Journal of Biological Chemistry.

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

[3]  M. Parisi,et al.  Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies , 1991, Nature.

[4]  P. Agris,et al.  Single atom modification (O-->S) of tRNA confers ribosome binding. , 1999, RNA.

[5]  X. Estivill,et al.  Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. , 2006, American journal of human genetics.

[6]  S. Osawa,et al.  Occurrence of unmodified adenine and uracil at the first position of anticodon in threonine tRNAs in Mycoplasma capricolum. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Takeshi Wada,et al.  Modified Uridines with C5-methylene Substituents at the First Position of the tRNA Anticodon Stabilize U·G Wobble Pairing during Decoding* , 2008, Journal of Biological Chemistry.

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

[9]  D. Wallace.  A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine , 2005, Annual review of genetics.

[10]  M. Barciszewska,et al.  The nucleotide in position 32 of the tRNA anticodon loop determines ability of anticodon UCC to discriminate among glycine codons. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Shamkant B. Navathe,et al.  MITOMAP: a human mitochondrial genome database—2004 update , 2004, Nucleic Acids Res..

[12]  Tsutomu Suzuki,et al.  Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  G. Kawai,et al.  A novel modified nucleoside found at the first position of the anticodon of methionine tRNA from bovine liver mitochondria. , 1994, Biochemistry.

[14]  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.

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

[16]  Takehiro Yasukawa,et al.  Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Sakuta,et al.  Accumulation of mtDNA with a mutation at position 3271 in tRNA(Leu)(UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function. , 1993, Biochemical and biophysical research communications.

[18]  T. Katoh,et al.  Biogenesis of glutaminyl-mt tRNAGln in human mitochondria , 2009, Proceedings of the National Academy of Sciences.

[19]  A. Harding,et al.  Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies , 1988, Nature.

[20]  L. Wangh,et al.  Single-Molecule LATE-PCR Analysis of Human Mitochondrial Genomic Sequence Variations , 2009, PloS one.

[21]  H. Jacobs,et al.  Human mtDNA sublimons resemble rearranged mitochondrial genoms found in pathological states. , 2000, Human molecular genetics.

[22]  D. Wallace,et al.  Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. , 1988, Science.

[23]  S. Yokoyama,et al.  1H NMR studies on the conformational characteristics of 2-thiopyrimidine nucleotides found in transfer RNAs. , 1979, Nucleic acids research.

[24]  M. Zeviani,et al.  Complex I deficiency is associated with 3243G:C mitochondrial DNA in osteosarcoma cell cybrids. , 1996, Human molecular genetics.

[25]  N. Bresolin,et al.  Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. , 1999, Science.

[26]  J. Enríquez,et al.  The Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episode Syndrome-associated Human Mitochondrial tRNALeu(UUR) Mutation Causes Aminoacylation Deficiency and Concomitant Reduced Association of mRNA with Ribosomes* , 2000, The Journal of Biological Chemistry.

[27]  S. Yokoyama,et al.  Molecular mechanism of codon recognition by tRNA species with modified uridine in the first position of the anticodon. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Shamkant B. Navathe,et al.  MITOMAP: a human mitochondrial genome database--1998 update , 1998, Nucleic Acids Res..

[29]  D. Wallace.  Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. , 2007, Annual review of biochemistry.

[30]  H. Jacobs,et al.  Genotypic stability, segregation and selection in heteroplasmic human cell lines containing np 3243 mutant mtDNA. , 2000, Genetics.

[31]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[32]  D. Söll,et al.  Biological function of 2-thiouridine in Escherichia coli glutamic acid transfer ribonucleic acid. , 1973, Biochemistry.

[33]  Tsutomu Suzuki,et al.  Chaplet column chromatography: isolation of a large set of individual RNAs in a single step. , 2007, Methods in enzymology.

[34]  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.

[35]  T. Rosenberg,et al.  An mtDNA mutation, 14453G→A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome , 2001, European Journal of Human Genetics.

[36]  M. King,et al.  The pathogenic A3243G mutation in human mitochondrial tRNALeu(UUR) decreases the efficiency of aminoacylation. , 2003, Biochemistry.

[37]  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.

[38]  C. Florentz,et al.  A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to reduced 3'-end processing and CCA addition. , 2004, Journal of molecular biology.

[39]  I. Nonaka,et al.  Findings in muscle in complex I (NADH coenzyme Q reductase) deficiency , 1988, Annals of neurology.

[40]  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.

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

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

[43]  A. Harding,et al.  A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. , 1990, American journal of human genetics.

[44]  T. Ohama,et al.  Translation of synonymous codons in family boxes by Mycoplasma capricolum tRNAs with unmodified uridine or adenosine at the first anticodon position. , 1995, Journal of molecular biology.

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

[46]  C. Epstein,et al.  Familial mitochondrial encephalomyopathy (MERRF): Genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease , 1988, Cell.

[47]  K. Nihei,et al.  A point mutation in the mitochondrial tRNA(Leu)(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). , 1990, Biochemical and biophysical research communications.

[48]  C. Florentz,et al.  Aminoacylation properties of pathology-related human mitochondrial tRNA(Lys) variants. , 2004, RNA.

[49]  K. Yarasheski,et al.  Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[50]  H. Reichmann,et al.  Pathophysiology of the MELAS 3243 Transition Mutation* , 1997, The Journal of Biological Chemistry.

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

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

[53]  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.

[54]  Tsutomu Suzuki,et al.  Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases , 2002, The EMBO journal.

[55]  G. Coruzzi,et al.  Codon recognition rules in yeast mitochondria. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Henri Grosjean,et al.  Fine-tuning of RNA functions by modification and editing , 2005 .

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

[58]  H. Jacobs,et al.  A tRNA suppressor mutation in human mitochondria , 1998, Nature Genetics.

[59]  Tsutomu Suzuki,et al.  The pathogenic A4269G mutation in human mitochondrial tRNAIle alters the T‐stem structure and decreases the binding affinity for elongation factor Tu , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[60]  H. Mandel,et al.  Acute infantile liver failure due to mutations in the TRMU gene. , 2009, American journal of human genetics.

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

[62]  Y. Goto,et al.  A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). , 1991, Biochimica et biophysica acta.

[63]  A. Raap,et al.  The A3243G tRNALeu(UUR) mutation induces mitochondrial dysfunction and variable disease expression without dominant negative acting translational defects in complex IV subunits at UUR codons. , 2007, Human molecular genetics.

[64]  M. Ibba,et al.  Pathogenic mechanism of a human mitochondrial tRNAPhe mutation associated with myoclonic epilepsy with ragged red fibers syndrome , 2007, Proceedings of the National Academy of Sciences.