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The ins and outs of mitochondrial iron-loading: the metabolic defect in Friedreich’s ataxia

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Abstract

Friedreich’s ataxia is a cardio- and neurodegenerative disease due to decreased expression of the mitochondrial protein, frataxin. This defect results in mitochondrial iron-overload, and in this review, we discuss the mechanisms that lead to this iron accumulation. Using a conditional knockout mouse model where frataxin is deleted in the heart, it has been shown that this mutation leads to transferrin receptor-1 upregulation, resulting in increased iron uptake from transferrin. There is also marked downregulation of ferritin that is required for iron storage and decreased expression of the iron exporter, ferroportin1, leading to decreased cellular iron efflux. The increased mitochondrial iron uptake is facilitated by upregulation of the mitochondrial iron transporter, mitoferrin2. This stimulation of iron uptake probably attempts to rescue the deficit in mitochondrial iron metabolism that is due to downregulation of mitochondrial iron utilization, namely, heme and iron–sulfur cluster (ISC) synthesis and also iron storage (mitochondrial ferritin). The resultant decrease in heme and ISC synthesis means heme and ISCs are not exiting the mitochondrion for cytosolic use. Hence, increased mitochondrial iron uptake coupled with decreased utilization and release leads to mitochondrial iron-loading. More generally, disturbance of mitochondrial iron utilization in other diseases probably also results in similar compensatory alterations.

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Acknowledgments

Work from the author's laboratory reported in this publication was supported by grants to D.R.R. including a Senior Principal Research Fellowship and Project Grant from the National Health and Medical Research Council of Australia; grants from the Muscular Dystrophy Association USA and NSW and Friedreich’s Ataxia Research Alliance Australia. M.L-H.H. and M.W. were supported by Ph.D Scholarships from the Friedreich’s Ataxia Research Alliance USA and University of Sydney (Australian Post-graduate Award), respectively. Y.S.R was supported by a Cancer Institute New South Wales Early Career Development Fellowship. P.P. thanks the Canadian Institutes of Health Research for a research grant.

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Authors and Affiliations

  1. Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW, 2006, Australia

    Des R. Richardson, Michael L-H. Huang, Megan Whitnall, Erika M. Becker & Yohan Suryo Rahmanto

  2. Lady Davis Institute for Medical Research, 3755 Cote Ste Catherine Rd, Montreal, H3T 1E2, QC, Canada

    Prem Ponka

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  1. Des R. Richardson
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Correspondence to Des R. Richardson.

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Richardson, D.R., Huang, M.LH., Whitnall, M. et al. The ins and outs of mitochondrial iron-loading: the metabolic defect in Friedreich’s ataxia. J Mol Med 88, 323–329 (2010). https://doi.org/10.1007/s00109-009-0565-x

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