title: The ins and outs of mitochondrial iron-loading: the metabolic defect in Friedreich's ataxia.
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, ferroportin 1, leading to decreased cellular iron efflux. The increased mitochondrial iron uptake is facilitated by upregulation of the mitochondrial iron transporter, mitoferrin 2. 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.
authors.affiliation: Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW, 2006, Australia. d.richardson@med.usyd.edu.au
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Michael L-H
authors.initials: ML
authors.lastname: Huang
authors.forename: Megan
authors.initials: M
authors.lastname: Whitnall
authors.forename: Erika M
authors.initials: EM
authors.lastname: Becker
authors.forename: Prem
authors.initials: P
authors.lastname: Ponka
authors.forename: Yohan
authors.initials: Y
authors.lastname: Suryo Rahmanto
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D005621:Friedreich Ataxia / Q000378:metabolism*; D006418:Heme / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000737:chemistry; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D011990:Receptors, Transferrin / Q000378:metabolism; D000096923:Frataxin; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D006418:Heme; D007501:Iron; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D011990:Receptors, Transferrin; D000096923:Frataxin; D000098742:Ferroportin