Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice.
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.
Thierbach
René
R
German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal-Berlin, and Charité University Medicine, Berlin, Germany.
Schulz
Tim J
TJ
Isken
Frank
F
Voigt
Anja
A
Mietzner
Brun
B
Drewes
Gunnar
G
von Kleist-Retzow
Jürgen-Christoph
JC
Wiesner
Rudolf J
RJ
Magnuson
Mark A
MA
Puccio
Hélène
H
Pfeiffer
Andreas F H
AF
Steinberg
Pablo
P
Ristow
Michael
M
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
D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D000096923:Frataxin