title: Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia.
abstract: 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.
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Shannon
authors.initials: S
authors.lastname: Chiang
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sahni
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Darius J R
authors.initials: DJ
authors.lastname: Lane
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Merlot
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia d.richardson@med.usyd.edu.au michael.huang@sydney.edu.au).
authors.forename: Michael L-H
authors.initials: ML
authors.lastname: Huang
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia d.richardson@med.usyd.edu.au michael.huang@sydney.edu.au).
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000818:Animals; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000096923:Frataxin
chemical_list: D007501:Iron; D033862:Iron-Binding Proteins; D000096923:Frataxin
keywords: frataxin; iron dys-regulation; mitochondrial iron processing; nuclear factor erythroid 2-related factor 2 (Nrf2); oxidative stress