Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation

Sheela Prithivirajsingh, Michael D. Story, Sherry A. Bergh, Fady B. Geara, K. Kian Ang, Sheikh M. Ismail, Craig W. Stevens, Thomas A. Buchholz, William A. Brock

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

Point mutations and deletions in mitochondrial DNA (mtDNA) accumulate as a result of oxidative stress, including ionizing radiation. As a result, dysfunctional mitochondria suffer from a decline in oxidative phosphorylation and increased release of superoxides and other reactive oxygen species (ROS). Through this mechanism, mitochondria have been implicated in a host of degenerative diseases. Associated with this type of damage, and serving as a marker of total mtDNA mutations and deletions, the accumulation of a specific 4977-bp deletion, known as the common deletion (Δ-mtDNA4977), takes place. The Δ-mtDNA4977 has been reported to increase with age and during the progression of mitochondrial degeneration. The purpose of this study was to investigate whether ionizing radiation induces the formation of the common deletion in a variety of human cell lines and to determine if it is associated with cellular radiosensitivity. Cell lines used included eight normal human skin fibroblast lines, a radiosensitive non-transformed and an SV40 transformed ataxia telangiectasia (AT) homozygous fibroblast line, a Kearns Sayre Syndrome (KSS) line known to contain mitochondrial deletions, and five human tumor lines. The Δ-mtDNA4977 was assessed by polymerase chain reaction (PCR). Significant levels of Δ-mtDNA4977 accumulated 72 h after irradiation doses of 2, 5, 10 or 20 Gy in all of the normal lines with lower response in tumor cell lines, but the absolute amounts of the induced deletion were variable. There was no consistent dose-response relationship. SV40 transformed and non-transformed AT cell lines both showed significant induction of the deletion. However, the five tumor cell lines showed only a modest induction of the deletion, including the one line that was deficient in DNA damage repair. No relationship was found between sensitivity to radiation-induced deletions and sensitivity to cell killing by radiation.

Original languageEnglish (US)
Pages (from-to)227-232
Number of pages6
JournalFEBS Letters
Volume571
Issue number1-3
DOIs
StatePublished - Jul 30 2004

Keywords

  • AT, ataxia telangiectasia
  • IR, ionizing radiation
  • Ionizing radiation
  • KSS, Kearns Sayre Syndrome
  • Mutation and common deletion
  • PCR
  • PCR, polymerase chain reaction
  • ROS, reactive oxygen species
  • SF, survival fraction
  • mtDNA
  • mtDNA, mitochondrial DNA

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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  • Cite this

    Prithivirajsingh, S., Story, M. D., Bergh, S. A., Geara, F. B., Kian Ang, K., Ismail, S. M., Stevens, C. W., Buchholz, T. A., & Brock, W. A. (2004). Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation. FEBS Letters, 571(1-3), 227-232. https://doi.org/10.1016/j.febslet.2004.06.078