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Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3331-3342
DOI: 10.1093/hmg/ddg349
© 2003 Oxford University Press

Reduction in frataxin causes progressive accumulation of mitochondrial damage

Gopalakrishnan Karthikeyan1, Janine H. Santos1, Maria A. Graziewicz1, William C. Copeland1, Grazia Isaya2, Bennett Van Houten1 and Michael A. Resnick1,*

1Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA and 2Departments of Pediatric and Adolescent Medicine and Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, MN 55905, USA

Received August 6, 2003; Accepted October 9, 2003

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.

* To whom correspondence should be addressed at: National Institute of Environmental Health Sciences (NIEHS), Mail Drop D3-01, 111 Alexander Drive, Research Triangle Park, NC 27709, USA. Tel: +1 9195414480; Fax: +1 9195417593; Email: resnick{at}niehs.nih.gov


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