Reduction in frataxin causes progressive accumulation of mitochondrial damage

Gopalakrishnan Karthikeyan, Janine H. Santos, Maria A. Graziewicz, William C. Copeland, Grazia Isaya, Bennett Van Houten, Michael A. Resnick

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Frataxin protein controls iron availability in mitochondria and reduced levels lead to the human disease, Friedreich's ataxia (FRDA). The molecular aspects of disease progression are not well understood. We developed a highly regulatable promoter system for expressing frataxin in yeast to address the consequences of chronically reduced amounts of this protein. Shutting off the promoter resulted in changes normally associated with loss of frataxin including iron accumulation within the mitochondria and the induction of mitochondrial petite mutants. While there was considerable oxidative damage to mitochondrial proteins, the petites were likely due to accumulation of mitochondrial DNA lesions and subsequent DNA loss. Chronically reduced frataxin levels resulted in similar response patterns. Furthermore, nuclear DNA damage was detected in a rad52 mutant, deficient in double-strand break repair. We conclude that reduced frataxin levels, which is more representative of the disease state, results in considerable oxidative damage in both mitochondrial and nuclear DNA.

Original languageEnglish (US)
Pages (from-to)3331-3342
Number of pages12
JournalHuman molecular genetics
Issue number24
StatePublished - Dec 15 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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