Human Molecular Genetics Advance Access published online on October 21, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg349
© 2003 by Oxford University Press
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1 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709
* To whom correspondence should be addressed. E-mail: resnick{at}niehs.nih.gov.
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.
Article
Reduction in frataxin causes progressive accumulation of mitochondrial damage
2 Departments of Pediatric and Adolescent Medicine and Biochemistry and Molecular Biology, Mayo Clinic & Foundation, Rochester MN 55905; Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences (NIEHS), Mail Drop D3-01, 111 Alexander Drive, Research Triangle Park, NC 27709
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