Human Molecular Genetics, Vol 8, 2255-2262, Copyright © 1999 by Oxford University Press
DM Gordon, Q Shi, A Dancis and D Pain
Friedreich's ataxia is a neurodegenerative disease caused by mutations in
the nuclear gene encoding frataxin (FRDA). FRDA is synthesized with an
N-terminal signal sequence, which is removed after import into
mitochondria. We have shown that FRDA was imported efficiently into
isolated mammalian or yeast mitochondria. In both cases, the processing
cleavage that removed the N-terminal signal sequence occurred in a single
step on import, generating mature products of identical mobility. The
processing cleavage could be reconstituted by incubating the FRDA
preprotein with rat or yeast matrix processing peptidase (MPP) expressed in
Escherichia coli. We used these assays to evaluate the import and
processing of an altered form of FRDA containing the disease- causing I154F
mutation. No effects on import or maturation of this mutated FRDA were
observed. Likewise, no effects were observed on import and maturation of
the yeast frataxin homolog (Yfh1p) carrying a homologous I130F mutation.
These results argue against the possibility that the I154F mutation
interferes with FRDA function via effects on maturation. Other mutations
can be screened for effects on FRDA biogenesis as described here, by
evaluating import into isolated mitochondria and by testing maturation with
purified MPP.
ARTICLES
Maturation of frataxin within mammalian and yeast mitochondria: one- step processing by matrix processing peptidase
Department of Physiology, University of Pennsylvania School of Medicine, D403 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085, USA and
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