The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron–sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.
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June 2016
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Mitochondrial protein quality control plays a decisive role in the maintenance of a proper mitochondrial function in metabolically active tissues such as skeletal muscle. Several chaperones and proteases, involved in the regulation of mitochondrial protein quality control, are altered in obesity and type 2 diabetes mellitus. For further details see Dahlmans et al. pp. 843–852.
Review Article|
April 22 2016
Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia
Shannon Chiang;
Shannon Chiang
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
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Zaklina Kovacevic;
Zaklina Kovacevic
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
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Sumit Sahni;
Sumit Sahni
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
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Darius J.R. Lane;
Darius J.R. Lane
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
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Angelica M. Merlot;
Angelica M. Merlot
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
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Danuta S. Kalinowski;
Danuta S. Kalinowski
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
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Michael L.-H. Huang;
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
Correspondence: Dr D.R. Richardson (email d.richardson@med.usyd.edu.au) or Dr M. L.-H. Huang (email michael.huang@sydney.edu.au).
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Des R. Richardson
*Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
Correspondence: Dr D.R. Richardson (email d.richardson@med.usyd.edu.au) or Dr M. L.-H. Huang (email michael.huang@sydney.edu.au).
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Publisher: Portland Press Ltd
Received:
December 17 2015
Revision Received:
February 16 2016
Accepted:
February 16 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (11): 853–870.
Article history
Received:
December 17 2015
Revision Received:
February 16 2016
Accepted:
February 16 2016
Citation
Shannon Chiang, Zaklina Kovacevic, Sumit Sahni, Darius J.R. Lane, Angelica M. Merlot, Danuta S. Kalinowski, Michael L.-H. Huang, Des R. Richardson; Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia. Clin Sci (Lond) 1 June 2016; 130 (11): 853–870. doi: https://doi.org/10.1042/CS20160072
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