TY - JOUR
T1 - Reduction in frataxin causes progressive accumulation of mitochondrial damage
AU - Karthikeyan, Gopalakrishnan
AU - Santos, Janine H.
AU - Graziewicz, Maria A.
AU - Copeland, William C.
AU - Isaya, Grazia
AU - Van Houten, Bennett
AU - Resnick, Michael A.
N1 - Funding Information:
We would like to thank Oleksander Gakh for the western blots with mitochondrial proteins for detecting frataxin, Mythreye Karthikeyan for help with the G2-arrested yeast cell pictures and Francoise Foury for the W303 strain. We also thank Homa Azargoon for technical assistance and Kevin Lewis and Jim Westmoreland for the development of the gal1* promoter and Greg Stuart and Ron Mason for critical reading of the manuscript. G.I. is funded by grant AG15709 from the NIH/NIA.
PY - 2003/12/15
Y1 - 2003/12/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddg349
DO - 10.1093/hmg/ddg349
M3 - Article
C2 - 14570713
AN - SCOPUS:0346752172
SN - 0964-6906
VL - 12
SP - 3331
EP - 3342
JO - Human molecular genetics
JF - Human molecular genetics
IS - 24
ER -