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 (1) , Andreas F H Pfeiffer , Pablo Steinberg , Michael Ristow

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

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.

Domaines: Biologie moléculaire

René Thierbach, Tim J Schulz, Frank Isken, Anja Voigt, Brun Mietzner, et al.. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice.. Human Molecular Genetics, 2005, 14 (24), pp.3857-64. ⟨10.1093/hmg/ddi410⟩. ⟨hal-00187779⟩