and Applied Analysis 3 (w3) for any ε > 0, there exists δ > 0 such that p(z, x) ≤ δ and p(z, y) ≤ δ imply d(x, y) ≤ ε. A function p : X×X → [0,∞) is said to be a τ-function [5, 10, 14, 15, 27–29], first introduced and studied by Lin and Du, if the following conditions hold: (τ1) p(x, z) ≤ p(x, y) + p(y, z) for all x, y, z ∈ X; (τ2) if x ∈ X and {yn} in X with limn→∞yn = y such that p(x, yn) ≤ M...

Background: Defects in the protein frataxin give rise to Friedreich ataxia. Results: A new Friedreich ataxia model using fission yeast has been generated, and its phenotype and proteome characterized. Conclusion: Frataxin absence triggers a complete iron starvation program, sufficient to generate all the associated respiratory defects. Significance: Our new model system may contribute to deciph...

The neurodegenerative disorder FRDA (Friedreich's ataxia) results from a deficiency in frataxin, a putative iron chaperone, and is due to the presence of a high number of GAA repeats in the coding regions of both alleles of the frataxin gene, which impair protein expression. However, some FRDA patients are heterozygous for this triplet expansion and contain a deleterious point mutation on the o...

It is well known that DNA replication affects the stability of several trinucleotide repeats, but whether replication profiles of human loci carrying an expanded repeat differ from those of normal alleles is poorly understood in the endogenous context. We investigated this issue using cell lines from Friedreich's ataxia patients, homozygous for a GAA-repeat expansion in intron 1 of the Frataxin...

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...

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich ataxia (FA). This disease is due to decreased expression of the mitochondrial protein, frataxin, which leads to alterations in mitochondrial iron (Fe) metabolism. The identification of potentially toxic mitochondrial Fe deposits in FA suggests Fe plays a role in its pathogenesis. Stu...

Friedreich's ataxia is a recessive neurodegenerative disease due to insufficient expression of the mitochondrial protein frataxin. Although it has been shown that frataxin is involved in the control of intracellular iron metabolism, by interfering with the mitochondrial biosynthesis of proteins with iron/sulphur (Fe/S) clusters its role has not been well established. We studied frataxin protein...

We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells ...

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...

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects individuals who are carriers of small CGG premutation expansions in the fragile X mental retardation 1 (FMR1) gene. Mitochondrial dysfunction was observed as an incipient pathological process occurring in individuals who do not display overt features of FXTAS (1). Fibroblasts from premuta...