Human Molecular Genetics, 2002, Vol. 11, No. 11 1351-1362
© 2002 Oxford University Press
The mitochondrial protein frataxin prevents nuclear damage
1Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, PO Box 12233, Research Triangle Park, NC 27709, USA and 2Department of Chemistry and Biochemistry, Southwest Texas State University, San Marcos, TX 78666, USA
Received February 26, 2002; Accepted March 13, 2002
The mitochondrial protein frataxin helps maintain appropriate iron levels in the mitochondria of yeast and humans. A deficiency of this protein in humans causes Friedreich's ataxia, while its complete absence in yeast (
yfh1 mutant) results in loss of mitochondrial DNA, apparently due to radicals generated by excess iron. We found that the absence of frataxin in yeast also leads to nuclear damage, as evidenced by inducibility of a nuclear DNA damage reporter, increased chromosomal instability including recombination and mutation, and greater sensitivity to DNA-damaging agents, as well as slow growth. Addition of a human frataxin mutant did not prevent nuclear damage, although it partially complemented the yfh1 mutant in preventing mitochondrial DNA loss. The effects in yfh1 mutants result from reactive oxygen species (ROS), since (i) yfh1 cells produce more hydrogen peroxide, (ii) the effects are alleviated by a radical scavenger and (iii) the glutathione peroxidase gene prevents an increase in mutation rates. Thus, the frataxin protein is concluded to have a protective role for the nucleus as well as the mitochondria.
* 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:+1 919 541 4480; Fax:+1 919 541 7593; Email: Resnick{at}NIEHS.NIH.GOV
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