title: Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells.
abstract: Organotin compounds, such as tributyltin (TBT), are well-known endocrine disruptors. TBT is also known to cause various forms of cytotoxicity, including neurotoxicity and immunotoxicity. However, TBT toxicity has not been identified in normal stem cells. In the present study, we examined the effects of TBT on cell growth in human induced pluripotent stem cells (iPSCs). We found that exposure to nanomolar concentrations of TBT decreased intracellular ATP levels and inhibited cell viability in iPSCs. Because TBT suppressed energy production, which is a critical function of the mitochondria, we further assessed the effects of TBT on mitochondrial dynamics. Staining with MitoTracker revealed that nanomolar concentrations of TBT induced mitochondrial fragmentation. TBT also reduced the expression of mitochondrial fusion protein mitofusin 1 (Mfn1), and this effect was abolished by knockdown of the E3 ubiquitin ligase membrane-associated RING-CH 5 (MARCH5), suggesting that nanomolar concentrations of TBT could induce mitochondrial dysfunction via MARCH5-mediated Mfn1 degradation in iPSCs. Thus, mitochondrial function in normal stem cells could be used to assess cytotoxicity associated with metal exposure.
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Japan; Faculty of Engineering, Department of Materials Science and Engineering, Yokohama National University, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Asanagi
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Hirata
authors.affiliation: Faculty of Engineering, Department of Materials Science and Engineering, Yokohama National University, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itagaki
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Japan. Electronic address: kanda@nihs.go.jp.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics*; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014220:Trialkyltin Compounds / Q000633:toxicity*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D034741:RNA, Small Interfering; D014220:Trialkyltin Compounds; C011559:tributyltin; D000255:Adenosine Triphosphate; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human
keywords: Induced pluripotent stem cells; Mitochondrial fission; Mitofusin; Tributyltin