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Human Molecular Genetics Advance Access originally published online on July 28, 2004
Human Molecular Genetics 2004 13(19):2279-2288; doi:10.1093/hmg/ddh232
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Human Molecular Genetics, Vol. 13, No. 19 © Oxford University Press 2004; all rights reserved

The expression of human mitochondrial ferritin rescues respiratory function in frataxin-deficient yeast

Alessandro Campanella1, Grazia Isaya2, Heather A. O'Neill2, Paolo Santambrogio1, Anna Cozzi1, Paolo Arosio3 and Sonia Levi1,*

1Department of Biological and Technological Research, IRCCS H. San Raffaele, Via Olgettina 58, Milano, 20132 Italy, 2Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA and 3Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, 25125 Italy

Received May 12, 2004; Accepted July 13, 2004

Mitochondrial ferritin (MtF) is structurally and functionally similar to the cytosolic ferritins, molecules designed to store and detoxify cellular iron. MtF expression in human and mouse is restricted to the testis and few tissues, and it is abundant in the erythroblasts of patients with sideroblastic anemia, where it is thought to protect the mitochondria from the damage caused by iron loading. Mitochondria iron overload occurs also in cells deficient in frataxin, a mitochondrial protein involved in iron handling and implicated in Friedreich ataxia. We expressed human MtF in frataxin-deficient yeast cells, a well-characterized model of mitochondrial iron overload and oxidative damage. The human MtF precursor was efficiently imported by yeast mitochondria and processed to functional ferritin that actively sequestered iron in the organelle. MtF expression rescued the respiratory deficiency caused by the loss of frataxin protecting the activity of iron–sulfur enzymes and enabling frataxin-deficient cells to grow on non-fermentable carbon sources. Furthermore, MtF expression prevented the development of mitochondrial iron overload, preserved mitochondrial DNA integrity and increased cell resistance to H2O2. The data show that MtF can substitute for most frataxin functions in yeast, suggesting that frataxin is directly involved in mitochondrial iron-binding and detoxification.

* To whom correspondence should be addressed. Tel: +39 0226464755; Fax: +39 0226434844; Email: levi.sonia{at}hsr.it


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