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.
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Ferritin H is a TNF-α- or IL-1-inducible gene.
“Ferritin H was found as a TNF-α– or IL-1–inducible gene (171, 243, 294).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [294]
Ferritin is the downstream mediator of the antioxidant and protective activities of NF-κB in response to TNF-α signaling in inflammation and apoptosis.
“Ferritin was identified as the downstream mediator of the antioxidant and protective activities of NF-κB in response to TNF-α signaling in inflammation and apoptosis (243, 294).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [294]
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- Authors
- Thierbach, R., Schulz, T. J., Isken, F., Voigt, A., Mietzner, B., Drewes, G., von Kleist-Retzow, J.-C., Wiesner, R. J., Magnuson, M. A., Puccio, H., Pfeiffer, A. F. H., Steinberg, P., & Ristow, M.
- Affiliations
- German Institute of Human Nutrition (DE)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Corresponding author
- Thierbach, René
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-11-08
- Volume
- 14
- Issue
- 24
- Pages
- 3857-3864
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2148930297
- Cited by
- 127
- References
- 53
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 4 · 2016: 4 · 2015: 4 · 2014: 2 · 2013: 9 · 2012: 10
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- publish.UP (University of Potsdam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- frataxin, Friedreich's ataxia, hepatocytes, mitochondrial dysfunction, oxidative phosphorylation, oxidative stress, iron-sulfur proteins, tumor suppressor, hepatocellular tumors, lifespan, p38 MAPK, apoptosis, hepatocyte proliferation, ATP levels, mitochondrial respiration
- MeSH terms
- Frataxin, Animals, Iron-Sulfur Proteins, Liver, Liver Neoplasms, Longevity, Mice, Inbred C57BL, Mitochondria, Phosphorylation, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Hepatocytes, Iron-Binding Proteins, p38 Mitogen-Activated Protein Kinases, Cell Proliferation, Mice
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