Impairment of mitochondrial tRNAIle processing by a novel mutation associated with chronic progressive external ophthalmoplegia

Mitochondrion. 2011 May;11(3):488-96. doi: 10.1016/j.mito.2011.01.005. Epub 2011 Feb 1.


We report a sporadic case of chronic progressive external ophthalmoplegia associated with ragged red fibers. The patient presented with enlarged mitochondria with deranged internal architecture and crystalline inclusions. Biochemical studies showed reduced activities of complex I, III and IV in skeletal muscle. Molecular genetic analysis of all mitochondrial tRNAs revealed a G to A transition at nt 4308; the G is a highly conserved nucleotide that participates in a GC base-pair in the T-stem of mammalian mitochondrial tRNA(Ile). The mutation was detected at a high level (approx. 50%) in muscle but not in blood. The mutation co-segregated with the phenotype, as the mutation was absent from blood and muscle in the patient's healthy mother. Functional characterization of the mutation revealed a six-fold reduced rate of tRNA(Ile) precursor 3' end maturation in vitro by tRNAse Z. Furthermore, the mutated tRNA(Ile) displays local structural differences from wild-type. These results suggest that structural perturbations reduce efficiency of tRNA(Ile) precursor 3' end processing and contribute to the molecular pathomechanism of this mutation.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex III / metabolism
  • Electron Transport Complex IV / metabolism
  • Female
  • Humans
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / pathology*
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / physiopathology
  • Ophthalmoplegia, Chronic Progressive External / genetics
  • Ophthalmoplegia, Chronic Progressive External / pathology*
  • Point Mutation*
  • RNA / genetics
  • RNA / metabolism
  • RNA Processing, Post-Transcriptional*
  • RNA, Mitochondrial
  • RNA, Transfer, Ile / genetics*
  • RNA, Transfer, Ile / metabolism*


  • RNA, Mitochondrial
  • RNA, Transfer, Ile
  • RNA
  • Electron Transport Complex IV
  • Electron Transport Complex I
  • Electron Transport Complex III