title: Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich's ataxia.
abstract: Friedreich's ataxia is the most important recessive ataxia in the Caucasian population. Loss of frataxin expression affects the production of iron-sulfur clusters and, therefore, mitochondrial energy production. One of the pathological consequences is an increase of iron transport into the mitochondrial compartment leading to a toxic accumulation of reactive iron. However, the mechanism underlying this inappropriate mitochondrial iron accumulation is still unknown. Control and frataxin-deficient flies were fed with an iron diet in order to mimic an iron overload and used to assess various cellular as well as mitochondrial functions. We showed that frataxin-deficient flies were hypersensitive toward dietary iron and developed an iron-dependent decay of mitochondrial functions. In the fly model exhibiting only partial frataxin loss, we demonstrated that the inability to activate ferritin translation and the enhancement of mitochondrial iron uptake via mitoferrin upregulation were likely the key molecular events behind the iron-induced phenotype. Both defects were observed during the normal process of aging, confirming their importance in the progression of the pathology. In an effort to further assess the importance of these mechanisms, we carried out genetic interaction studies. We showed that mitoferrin downregulation improved many of the frataxin-deficient conditions, including nervous system degeneration, whereas mitoferrin overexpression exacerbated most of them. Taken together, this study demonstrates the crucial role of mitoferrin dysfunction in the etiology of Friedreich's ataxia and provides evidence that impairment of mitochondrial iron transport could be an effective treatment of the disease.
authors.affiliation: Institute of Zoology, University of Regensburg, Universitaetsstrasse 31, 93040 Regensburg, Germany. Electronic address: juan.navarro@ur.de.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Navarro
authors.affiliation: Institute of Zoology, University of Regensburg, Universitaetsstrasse 31, 93040 Regensburg, Germany.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Botella
authors.affiliation: Biochemistry Center, Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Metzendorf
authors.affiliation: Department of Comparative Physiology, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Lind
authors.affiliation: Institute of Zoology, University of Regensburg, Universitaetsstrasse 31, 93040 Regensburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schneuwly
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000502:physiology*; D005621:Friedreich Ataxia / Q000235:genetics / Q000503:physiopathology*; D015870:Gene Expression; D007501:Iron / Q000633:toxicity*; D033862:Iron-Binding Proteins / Q000235:genetics; D000096923:Frataxin
chemical_list: D029721:Drosophila Proteins; D007501:Iron; D033862:Iron-Binding Proteins; D000096923:Frataxin; C543111:Mfrn protein, Drosophila
keywords: Brain degeneration; Drosophila melanogaster; Fer1HCH; Frataxin; Friedreich׳s ataxia; Iron overload; Mitoferrin