Human Molecular Genetics Advance Access first published online on November 8, 2005
This version published online on November 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi410
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Institute for Nutrition, Department of Nutritional Toxicology, University of Potsdam, Nuthetal-Berlin 14558, Germany
* To whom correspondence should be addressed. We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes in order to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation (OXPHOS). 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.
Received October 6, 2005
Accepted October 26, 2005
Article
Targeted Disruption of Hepatic Frataxin Expression Causes Impaired Mitochondrial Function, Decreased Life Span, and Tumor Growth in Mice
2 German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal-Berlin 14558, Germany
3 Charité University Medicine, Campus Benjamin Franklin, Berlin 12200, Germany
4 German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal-Berlin 14558, Germany; Institute for Nutrition, Department of Nutritional Toxicology, University of Potsdam, Nuthetal-Berlin 14558, Germany
5 Institute for Vegetative Physiology, University of Cologne, Cologne 50931, Germany; Clinic for Paediatric Medicine, University of Cologne, Cologne 50924, Germany; Centre for Molecular Medicine Cologne, University of Cologne, Cologne 50924, Germany
6 Institute for Vegetative Physiology, University of Cologne, Cologne 50931, Germany; Centre for Molecular Medicine Cologne, University of Cologne, Cologne 50924, Germany
7 Vanderbilt University, Nashville, TN 37232, USA
8 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67404, France
9 German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal-Berlin 14558, Germany; Charité University Medicine, Campus Benjamin Franklin, Berlin 12200, Germany
Michael Ristow, E-mail: michael.ristow{at}mristow.org
Abstract
The Advanced Access version of this article has been replaced because the original figures were not sized correctly in the pdf.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H.-Y. Liu, T. Hong, G.-B. Wen, J. Han, D. Zuo, Z. Liu, and W. Cao Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance Am J Physiol Endocrinol Metab, October 1, 2009; 297(4): E898 - E906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Coppola, D. Marmolino, D. Lu, Q. Wang, M. Cnop, M. Rai, F. Acquaviva, S. Cocozza, M. Pandolfo, and D. H. Geschwind Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR{gamma} pathway as a therapeutic target in Friedreich's ataxia Hum. Mol. Genet., July 1, 2009; 18(13): 2452 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Campanella, E. Rovelli, P. Santambrogio, A. Cozzi, F. Taroni, and S. Levi Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia Hum. Mol. Genet., January 1, 2009; 18(1): 1 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Schmucker, M. Argentini, N. Carelle-Calmels, A. Martelli, and H. Puccio The in vivo mitochondrial two-step maturation of human frataxin Hum. Mol. Genet., November 15, 2008; 17(22): 3521 - 3531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Son, S. C. Leary, N. Romain, F. Pierrel, D. R. Winge, R. G. Haller, and J. L. Elliott Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein J. Biol. Chem., May 2, 2008; 283(18): 12267 - 12275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Pomplun, A. Voigt, T. J. Schulz, R. Thierbach, A. F. Pfeiffer, and M. Ristow Reduced expression of mitochondrial frataxin in mice exacerbates diet-induced obesity PNAS, April 10, 2007; 104(15): 6377 - 6381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Zarse, T. J. Schulz, M. Birringer, and M. Ristow Impaired respiration is positively correlated with decreased life span in Caenorhabditis elegans models of Friedreich Ataxia FASEB J, April 1, 2007; 21(4): 1271 - 1275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. F. El-Khamisy and K. W. Caldecott TDP1-dependent DNA single-strand break repair and neurodegeneration Mutagenesis, July 1, 2006; 21(4): 219 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Condo, N. Ventura, F. Malisan, B. Tomassini, and R. Testi A Pool of Extramitochondrial Frataxin That Promotes Cell Survival J. Biol. Chem., June 16, 2006; 281(24): 16750 - 16756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Gakh, S. Park, G. Liu, L. Macomber, J. A. Imlay, G. C. Ferreira, and G. Isaya Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity Hum. Mol. Genet., February 1, 2006; 15(3): 467 - 479. [Abstract] [Full Text] [PDF]
|
|