Frataxin is a conserved mitochondrial protein deficient in patients with Friedreich's ataxia. Frataxin has been implicated in control of iron homoeostasis and Fe–S cluster assembly. In yeast or human mitochondria, frataxin interacts with components of the Fe–S cluster synthesis machinery, including the cysteine desulfurase Nfs1, accessory protein Isd11 and scaffold protein Isu. In the present paper, we report that a single amino acid substitution (methionine to isoleucine) at position 107 in the mature form of Isu1 restored many deficient functions in Δyfh1 or frataxin-depleted yeast cells. Iron homoeostasis was improved such that soluble/usable mitochondrial iron was increased and accumulation of insoluble/non-usable iron within mitochondria was largely prevented. Cytochromes were returned to normal and haem synthesis was restored. In mitochondria carrying the mutant Isu1 and no frataxin, Fe–S cluster enzyme activities were improved. The efficiency of new Fe–S cluster synthesis in isolated mitochondria was markedly increased compared with frataxin-negative cells, although the response to added iron was minimal. The M107I substitution in the highly conserved Isu scaffold protein is typically found in bacterial orthologues, suggesting that a unique feature of the bacterial Fe–S cluster machinery may be involved. The mechanism by which the mutant Isu bypasses the absence of frataxin remains to be determined, but could be related to direct effects on Fe–S cluster assembly and/or indirect effects on mitochondrial iron availability.
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Research Article|
December 14 2011
Mutation in the Fe–S scaffold protein Isu bypasses frataxin deletion
Heeyong Yoon;
Heeyong Yoon
*Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Ramesh Golla;
Ramesh Golla
*Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Emmanuel Lesuisse;
Emmanuel Lesuisse
†Laboratory of Mitochondria, Metals and Oxidative Stress, Institut Jacques Monod, CNRS–Université Paris Diderot, 75205, Paris Cedex 13, France
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Jayashree Pain;
Jayashree Pain
‡Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07101, U.S.A.
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Jason E. Donald;
Jason E. Donald
§Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Elise R. Lyver;
Elise R. Lyver
*Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Debkumar Pain;
Debkumar Pain
‡Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07101, U.S.A.
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Andrew Dancis
Andrew Dancis
1
*Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
1To whom correspondence should be addressed (email adancis@mail.med.upenn.edu).
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Publisher: Portland Press Ltd
Received:
September 08 2011
Accepted:
September 21 2011
Accepted Manuscript online:
September 21 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (1): 473–480.
Article history
Received:
September 08 2011
Accepted:
September 21 2011
Accepted Manuscript online:
September 21 2011
Citation
Heeyong Yoon, Ramesh Golla, Emmanuel Lesuisse, Jayashree Pain, Jason E. Donald, Elise R. Lyver, Debkumar Pain, Andrew Dancis; Mutation in the Fe–S scaffold protein Isu bypasses frataxin deletion. Biochem J 1 January 2012; 441 (1): 473–480. doi: https://doi.org/10.1042/BJ20111637
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