Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice |
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Authors: | Thierbach René Schulz Tim J Isken Frank Voigt Anja Mietzner Brun Drewes Gunnar von Kleist-Retzow Jürgen-Christoph Wiesner Rudolf J Magnuson Mark A Puccio Hélène Pfeiffer Andreas F H Steinberg Pablo Ristow Michael |
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Affiliation: | German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal-Berlin, and Charité University Medicine, Berlin, Germany. |
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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. |
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