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Human Molecular Genetics Advance Access originally published online on November 8, 2005
Human Molecular Genetics 2005 14(24):3857-3864; doi:10.1093/hmg/ddi410
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice

René Thierbach3,{dagger}, Tim J. Schulz1,{dagger}, Frank Isken2, Anja Voigt1,3, Brun Mietzner1, Gunnar Drewes1,3, Jürgen-Christoph von Kleist-Retzow4,5,6, Rudolf J. Wiesner4,6, Mark A. Magnuson7, Hélène Puccio8, Andreas F.H. Pfeiffer1,2, Pablo Steinberg3 and Michael Ristow1,2,*

1German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal-Berlin 14558, Germany, 2Charité University Medicine, Campus Benjamin Franklin, Berlin 12200, Germany, 3Department of Nutritional Toxicology, Institute for Nutrition, University of Potsdam, Nuthetal-Berlin 14558, Germany, 4Institute for Vegetative Physiology, University of Cologne, Cologne 50931, Germany, 5Clinic for Paediatric Medicine, University of Cologne, Cologne 50924, Germany, 6Centre for Molecular Medicine Cologne, University of Cologne, Cologne 50924, Germany, 7Vanderbilt University, Nashville, TN 37232, USA and 8Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67404, France

* To whom correspondence should be addressed at: Department of Human Nutrition, Institute for Nutrition, University of Jena, 29 Dornburger Street, Jena 07743, Germany. Tel: +49 3641949630; Fax: +49 3641949632; Email: michael.ristow{at}mristow.org

Received October 6, 2005; Accepted October 26, 2005

We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron–sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice
René Thierbach, Tim J. Schulz, Frank Isken, Anja Voigt, Brun Mietzner, Gunnar Drewes, Jürgen-Christoph von Kleist-Retzow, Rudolf J. Wiesner, Mark A. Magnuson, Hélène Puccio, Andreas F.H. Pfeiffer, Pablo Steinberg, and Michael Ristow
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