title: Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice.
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.
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal-Berlin, and Charité University Medicine, Berlin, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Thierbach
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Schulz
authors.forename: Frank
authors.initials: F
authors.lastname: Isken
authors.forename: Anja
authors.initials: A
authors.lastname: Voigt
authors.forename: Brun
authors.initials: B
authors.lastname: Mietzner
authors.forename: Gunnar
authors.initials: G
authors.lastname: Drewes
authors.forename: Jürgen-Christoph
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Hélène
authors.initials: H
authors.lastname: Puccio
authors.forename: Andreas F H
authors.initials: AF
authors.lastname: Pfeiffer
authors.forename: Pablo
authors.initials: P
authors.lastname: Steinberg
authors.forename: Michael
authors.initials: M
authors.lastname: Ristow
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008099:Liver / Q000473:pathology / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D000096923:Frataxin