The mitochondrial protein frataxin prevents nuclear damage.
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 (Delta 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 Delta yfh1 mutant in preventing mitochondrial DNA loss. The effects in Delta yfh1 mutants result from reactive oxygen species (ROS), since (i) Delta 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.
Karthikeyan
Gopalakrishnan
G
Laboratory of Molecular Genetics, National Institute of Enviromental Health Sciences, NIH, PO Box 12233, Research Triangle Park, NC 27709, USA.
Lewis
L Kevin
LK
Resnick
Michael A
MA
D000111:Acetylcysteine / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology; D012854:Sister Chromatid Exchange; D000096923:Frataxin
D000111:Acetylcysteine; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D006861:Hydrogen Peroxide; D007501:Iron; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin; C079091:APBA1 protein, human