Increased incidence of mitochondrial cytochrome c-oxidase gene mutations in patients with myelodysplastic syndromes

Br J Haematol. 2002 Mar;116(3):564-75. doi: 10.1046/j.0007-1048.2001.03323.x.


Mitochondria (mt) play an important role in both apoptosis and haem synthesis. The present study was conducted to determine DNA mutations in mitochondrial encoded cytochrome c-oxidase I and II genes. Bone marrow (BM) biopsy and aspirate, peripheral blood (PB) and buccal smear samples were collected from 20 myelodysplastic syndrome (MDS) patients and 10 age-matched controls. Cytochrome c-oxidase I (CO I) and II (CO II) genes were amplified using polymerase chain reaction and sequenced. CO I mutations were found in 13/20 MDS patients and the CO II gene in 2/10 normal and 12/20 MDS samples, irrespective of MDS subtype. Mutations were substitutional, deletional and insertional. CO I mutations were most common at nucleotide positions 7264 (25%) and 7289 (15%), and CO II mutations were most common at nucleotide positions 7595 (40%) and 7594 (30%), suggesting the presence of potential 'hot-spots'. Mutations were not found in buccal smears of MDS patients and were significantly higher in MDS samples compared with age-matched controls in all cell fractions (P < 0.05), with bone marrow high-density fraction (BMHDF) showing a higher mutation rate than other fractions (P < 0.05). MDS marrows showed higher levels of apoptosis than normal controls (P < 0.05), and apoptosis in BMHDF was directly related to cytochrome c-oxidase I gene mutations (P < 0.05). Electron microscopy revealed apoptosis affecting all haematopoietic lineages with highly abnormal, iron-laden mitochondria. These results suggest a role for mt-DNA mutations in the excessive apoptosis and resulting cytopenias of MDS patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis
  • Bone Marrow Cells / enzymology
  • Bone Marrow Cells / ultrastructure
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex IV / genetics*
  • Female
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Middle Aged
  • Mitochondria / enzymology*
  • Mitochondria / ultrastructure
  • Mutation*
  • Myelodysplastic Syndromes / enzymology
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / pathology


  • DNA, Mitochondrial
  • Electron Transport Complex IV