Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation

Nucleic Acids Res. 2008 May;36(9):3065-74. doi: 10.1093/nar/gkn147. Epub 2008 Apr 8.


Phenotypic diversity associated with pathogenic mutations of the human mitochondrial genome (mtDNA) has often been explained by unequal segregation of the mutated and wild-type genomes (heteroplasmy). However, this simple hypothesis cannot explain the tissue specificity of disorders caused by homoplasmic mtDNA mutations. We have previously associated a homoplasmic point mutation (1624C>T) in MTTV with a profound metabolic disorder that resulted in the neonatal deaths of numerous siblings. Affected tissues harboured a marked biochemical defect in components of the mitochondrial respiratory chain, presumably due to the extremely low (<1%) steady-state levels of mt-tRNA(Val). In primary myoblasts and transmitochondrial cybrids established from the proband (index case) and offspring, the marked respiratory deficiency was lost and steady-state levels of the mutated mt-tRNA(Val) were greater than in the biopsy material, but were still an order of magnitude lower than in control myoblasts. We present evidence that the generalized decrease in steady-state mt-tRNA(Val) observed in the homoplasmic 1624C>T-cell lines is caused by a rapid degradation of the deacylated form of the abnormal mt-tRNA(Val). By both establishing the identity of the human mitochondrial valyl-tRNA synthetase then inducing its overexpression in transmitochondrial cell lines, we have been able to partially restore steady-state levels of the mutated mt-tRNA(Val), consistent with an increased stability of the charged mt-tRNA. These data indicate that variations in the levels of VARS2L between tissue types and patients could underlie the difference in clinical presentation between individuals homoplasmic for the 1624C>T mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • Cells, Cultured
  • HLA Antigens / metabolism*
  • Humans
  • Mitochondria / enzymology
  • Mitochondrial Myopathies / genetics*
  • Mitochondrial Proteins / metabolism*
  • Molecular Sequence Data
  • Point Mutation*
  • RNA / chemistry
  • RNA / genetics*
  • RNA / metabolism
  • RNA Stability
  • RNA, Mitochondrial
  • RNA, Transfer, Val / chemistry
  • RNA, Transfer, Val / genetics*
  • RNA, Transfer, Val / metabolism
  • Valine-tRNA Ligase / metabolism*


  • HLA Antigens
  • Mitochondrial Proteins
  • RNA, Mitochondrial
  • RNA, Transfer, Val
  • VARS2 protein, human
  • RNA
  • Valine-tRNA Ligase