The mitochondrial protein frataxin prevents nuclear damage

Abstract

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 (Dyfh1 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 Dyfh1 mutant in preventing mitochondrial DNA loss. The effects in Dyfh1 mutants result from reactive oxygen species (ROS), since (i) Dyfh1 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.

Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth

“…Frataxin has been described to reduce accumulation of ROS when overexpressed in non-transformed fibroblasts (16), and its yeast homologue Yfh1 has been shown to prevent damage to nuclear as well as mitochondrial DNA in Saccharomyces cerevisiae (17,18). Furthermore, mice lacking frataxin in pancreatic ␤ cells (23) or hepatocytes 4 exhibit an increased expression of oxidative stress markers.…”

“…Several groups have previously shown that frataxin may influence the formation and accumulation of ROS in yeast, cultured mammalian cells, rodents, and finally humans (13)(14)(15)(16)(17)(18)23). Nevertheless, recent findings question the primary relevance of ROS formation in frataxin deficiency (25).…”

“…Overexpression of frataxin has been shown to reduce intracellular accumulation of reactive oxygen species (ROS) 3 and to prevent menadione-induced malignant transformation of fibroblasts (16). Furthermore, disruption of the frataxin homologue in yeast has been shown to cause increased sensitivity to oxidants and promote oxidative damage to both nuclear (17), as well as mitochondrial, DNA (18). In addition, fibroblasts from Friedreich ataxia patients exhibit increased sensitivity against ionizing radiation and show an increased frequency of transforming events (19).…”

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

“…2). Moreover, it is found that DNA damage-inducible nuclear genes were highly expressed in cells lacking frataxin, suggesting that frataxin has a protective role in the nucleus and mitochondria to detoxify reactive oxygen species (Karthikeyan et al 2002).…”

The Ferroxidase Activity of Yeast Frataxin

“…Frataxin was first identified as the protein deficient in Friedreich ataxia, a neuro-and cardiodegenerative disease (12). Studies in Saccharomyces cerevisiae have shown that defects in yeast or human frataxin are associated with the accumulation of iron in mitochondria and oxidative damage to both mitochondrial and nuclear DNA as well as to the iron-sulfur centers of mitochondrial aconitase and other respiratory enzymes (10,14,15,34). Similarly, mouse models in which the frataxin gene is selectively inactivated in neuronal or cardiac tissue present multiple respiratory enzyme deficits and accumulate iron in mitochondria in a time-dependent manner (16).…”