Novel Frataxin Isoforms May Contribute to the Pathological Mechanism of Friedreich Ataxia

Abstract

Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum-specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA.

Missense Mutations Linked to Friedreich Ataxia Have Different but Synergistic Effects on Mitochondrial Frataxin Isoforms

“…Both isoforms are normally present in cultured cells and tissues and are thought to ensure incremental rates of iron-sulfur cluster synthesis depending on iron availability and metabolic requirements (8). Extra-mitochondrial isoforms of FXN have also been identified (20 -22); they appear to originate from alternative splicing of the FRDA transcript and may participate in ironsulfur cluster synthesis and/or antioxidant protection in the cytoplasm and the nucleus (21,22).…”

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

“…In addition to the size of the GAA repeat expansions and the focal localised iron deposits in the heart and brain, other such factors include the possibility of frataxin isoforms, distribution of iron in other tissues or organs, dietary habits and many other [62,63,93] . The pathogenesis of the disease and the high level of toxicity observed mainly in the heart and the brain of FA patients may also be related to the high requirements and consumption but insufficient utilization of oxygen due to mitochondrial malfunctioning in these main target organs.…”

Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms

“…Isoform amplifications were performed in a 25-μl PCR using 1 μl of the resulting cDNA using the same primers as described by Xia and colleagues [44], except for the amplification of isoform III, for which a specific forward primer was designed spanning exon1AΔ141/exon 2 junction (5′-GGCGCCGCGCAGTTCGAACC-3′). Fig.…”

“…Interestingly, a recent report has highlighted the existence of two novel frataxin isoforms (FXN II and FXN III) which lack the mitochondrial targeting sequence and may also play a role in the pathogenesis of FRDA [44]. Thus, in addition to the canonical frataxin (FXN I) form which is found within mitochondria, FXN III, generated by alternative splicing, is localised to cell nuclei and FXN II, generated by a different transcription start site, is present in the cytosol [44]. Interestingly the expression of FXN II is particularly significant in the nervous tissue including the cerebellum whereas FXN III seems more enriched in the heart [44].…”

“…Thus, in addition to the canonical frataxin (FXN I) form which is found within mitochondria, FXN III, generated by alternative splicing, is localised to cell nuclei and FXN II, generated by a different transcription start site, is present in the cytosol [44]. Interestingly the expression of FXN II is particularly significant in the nervous tissue including the cerebellum whereas FXN III seems more enriched in the heart [44].…”