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Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes.

Abstract：

:Frataxin is a highly conserved protein encoded by the frataxin (FXN) gene. The full-length 210-amino acid form of protein frataxin (1-210; isoform A) expressed in the cytosol of cells rapidly translocates to the mitochondria, where it is converted to the mature form (81-210) by mitochondrial processing peptidase. Mature frataxin (81-210) is a critically important protein because it facilitates the assembly of mitochondrial iron-sulfur cluster protein complexes such as aconitase, lipoate synthase, and succinate dehydrogenases. Decreased expression of frataxin protein is responsible for the devastating rare genetic disease of Friedreich's ataxia. The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich's ataxia and monitor the efficacy of therapeutic interventions.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Guo L,Wang Q,Weng L,Hauser LA,Strawser CJ,Mesaros C,Lynch DR,Blair IA

doi

10.1038/s41598-018-35346-y

subject

Has Abstract

pub_date

2018-11-19 00:00:00

pages

17043

issue

issn

2045-2322

pii

10.1038/s41598-018-35346-y

journal_volume

pub_type

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Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes.