Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells

Shigeru Yamada, Miki Asanagi, Naoya Hirata, Hiroshi Itagaki, Yuko Sekino, Yasunari Kanda

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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.

Original languageEnglish
Pages (from-to)257-263
Number of pages7
JournalToxicology in Vitro
Volume34
DOIs
StatePublished - 2016 Aug 1

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Mitochondrial Dynamics
Induced Pluripotent Stem Cells
Stem Cells
Membranes
Organotin Compounds
Endocrine Disruptors
Ubiquitin-Protein Ligases
Mitochondrial Proteins
Cell Survival
Mitochondria
Adenosine Triphosphate
Metals
Staining and Labeling

Keywords

  • Induced pluripotent stem cells
  • Mitochondrial fission
  • Mitofusin
  • Tributyltin

ASJC Scopus subject areas

  • Toxicology

Cite this

Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells. / Yamada, Shigeru; Asanagi, Miki; Hirata, Naoya; Itagaki, Hiroshi; Sekino, Yuko; Kanda, Yasunari.

In: Toxicology in Vitro, Vol. 34, 01.08.2016, p. 257-263.

Research output: Contribution to journalArticle

Yamada, Shigeru; Asanagi, Miki; Hirata, Naoya; Itagaki, Hiroshi; Sekino, Yuko; Kanda, Yasunari / Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells.

In: Toxicology in Vitro, Vol. 34, 01.08.2016, p. 257-263.

Research output: Contribution to journalArticle

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AU - Asanagi,Miki

AU - Hirata,Naoya

AU - Itagaki,Hiroshi

AU - Sekino,Yuko

AU - Kanda,Yasunari

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AB - 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.

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