The in vivo mitochondrial two-step maturation of human frataxin. - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Human Molecular Genetics Year : 2008

The in vivo mitochondrial two-step maturation of human frataxin.


Deficiency in the nuclear-encoded mitochondrial protein frataxin causes Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associating spinocerebellar ataxia and cardiomyopathy. Although the exact function of frataxin is still a matter of debate, it is widely accepted that frataxin is a mitochondrial iron chaperone involved in iron-sulfur cluster and heme biosynthesis. Frataxin is synthesized as a precursor polypeptide, directed to the mitochondrial matrix where it is proteolytically cleaved by the mitochondrial processing peptidase to the mature form via a processing intermediate. The mature form was initially reported to be encoded by amino acids 56-210 (m(56)-FXN). However, two independent reports have challenged these studies describing two different forms encoded by amino acids 78-210 (m(78)-FXN) and 81-210 (m(81)-FXN). Here, we provide evidence that mature human frataxin corresponds to m(81)-FXN, and can rescue the lethal phenotype of fibroblasts completely deleted for frataxin. Furthermore, our data demonstrate that the migration profile of frataxin depends on the experimental conditions, a behavior which most likely contributed to the confusion concerning the endogenous mature frataxin. Interestingly, we show that m(56)-FXN and m(78)-FXN can be generated when the normal maturation process of frataxin is impaired, although the physiological relevance is not clear. Furthermore, we determine that the d-FXN form, previously reported to be a degradation product, corresponds to m(78)-FXN. Finally, we demonstrate that all frataxin isoforms are generated and localized within the mitochondria. The clear identification of the N-terminus of mature FXN is an important step for designing therapeutic approaches for FRDA based on frataxin replacement.

Dates and versions

inserm-00350838 , version 1 (07-01-2009)



Stéphane Schmucker, Manuela Argentini, Nadège Carelle-Calmels, Alain Martelli, Hélène Puccio. The in vivo mitochondrial two-step maturation of human frataxin.. Human Molecular Genetics, 2008, 17 (22), pp.3521-31. ⟨10.1093/hmg/ddn244⟩. ⟨inserm-00350838⟩
55 View
0 Download



Gmail Facebook X LinkedIn More