Authors: Thierbach R; Schulz TJ; Isken F; Voigt A; Mietzner B; Drewes G; von Kleist-Retzow JC; Wiesner RJ; Magnuson MA; Puccio H; Pfeiffer AF; Steinberg P; Ristow M
Abstract: 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.
Keywords: Animals; Apoptosis/genetics; Cell Proliferation; Hepatocytes/metabolism/pathology; Iron-Binding Proteins/*genetics/metabolism; Iron-Sulfur Proteins/metabolism; Liver/pathology/*physiology; Liver Neoplasms/*genetics/pathology; Longevity/*genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria/genetics/*metabolism; Oxidative Stress; Phosphorylation; Reactive Oxygen Species/metabolism; p38 Mitogen-Activated Protein Kinases/metabolism|
Journal: Human molecular genetics Volume: 14 Issue: 24 Pages: 3857-64 Date: Nov. 10, 2005 PMID: 16278235 |
Thierbach R, Schulz TJ, Isken F, Voigt A, Mietzner B, Drewes G, von Kleist-Retzow JC, Wiesner RJ, Magnuson MA, Puccio H, Pfeiffer AF, Steinberg P, Ristow M (2005) Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Human molecular genetics 14: 3857-64.
Comment on This Data Unit