title: Lack of mitochondrial topoisomerase I (TOP1mt) impairs liver regeneration.
abstract: The liver has an exceptional replicative capacity following partial hepatectomy or chemical injuries. Cellular proliferation requires increased production of energy and essential metabolites, which critically depend on the mitochondria. To determine whether Top1mt, the vertebrate mitochondrial topoisomerase, is involved in this process, we studied liver regeneration after carbon tetrachloride (CCl4) administration. TOP1mt knockout (KO) mice showed a marked reduction in regeneration and hepatocyte proliferation. The hepatic mitochondrial DNA (mtDNA) failed to increase during recovery from CCl4 exposure. Reduced glutathione was also depleted, indicating increased reactive oxygen species (ROS). Steady-state levels of ATP, O2 consumption, mtDNA, and mitochondrial mass were also reduced in primary hepatocytes from CCl4-treated KO mice. To further test whether Top1mt acted by enabling mtDNA regeneration, we tested TOP1mt KO fibroblasts and human colon carcinoma HCT116 cells and measured mtDNA after 3-d treatment with ethidium bromide. Both types of TOP1mt knockout cells showed defective mtDNA regeneration following mtDNA depletion. Our study demonstrates that Top1mt is required for normal mtDNA homeostasis and for linking mtDNA expansion with hepatocyte proliferation.
authors: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Salim
authors: S
authors: Khiati
authors: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Simone A
authors: SA
authors: Baechler
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Valentina M
authors: VM
authors: Factor
authors: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Hongliang
authors: H
authors: Zhang
authors: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Shar-yin N
authors: SY
authors: Huang
authors: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Ilaria
authors: I
authors: Dalla Rosa
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Carole
authors: C
authors: Sourbier
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Leonard
authors: L
authors: Neckers
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Snorri S
authors: SS
authors: Thorgeirsson
authors: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; pommier@nih.gov.
authors: Yves
authors: Y
authors: Pommier
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D005978:Glutathione / Q000378:metabolism; D045325:HCT116 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D004264:DNA Topoisomerases, Type I; D005978:Glutathione
keywords: cell proliferation; liver regeneration; mitochondrial DNA replication; mitochondrial homeostasis; mitochondrial topoisomerase I