Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells.
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.
['Yamada|Shigeru|S|', 'Asanagi|Miki|M|', 'Hirata|Naoya|N|', 'Itagaki|Hiroshi|H|', 'Sekino|Yuko|Y|', 'Kanda|Yasunari|Y|']
D000255:Adenosine Triphosphate D002460:Cell Line D049109:Cell Proliferation D002470:Cell Survival D020558:GTP Phosphohydrolases D006801:Humans D057026:Induced Pluripotent Stem Cells D053078:Membrane Potential, Mitochondrial D008565:Membrane Proteins D063154:Mitochondrial Dynamics D033681:Mitochondrial Membrane Transport Proteins D034741:RNA, Small Interfering D014220:Trialkyltin Compounds D044767:Ubiquitin-Protein Ligases
Tributyltin Mitochondrial fission Induced pluripotent stem cells Mitofusin