Novel frataxin isoforms may contribute to the pathological mechanism of Friedreich ataxia.
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.
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
Haiyan
H
Xia
Yun
Y
Cao
Xiaoman
X
Dai
Zvonimir
Z
Marelja
Di
D
Zhou
Ran
R
Mo
Sahar
S
Al-Mahdawi
Mark A
MA
Pook
Silke
S
Leimkühler
Tracey A
TA
Rouault
Kuanyu
K
Li
D000328:Adult; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D000096923:Frataxin