title: Tributyltin induces mitochondrial fission through NAD-IDH dependent mitofusin degradation in human embryonic carcinoma cells.
abstract: Organotin compounds, such as tributyltin (TBT), are well-known endocrine disruptors. TBT acts at the nanomolar level through genomic pathways via the peroxisome proliferator activated receptor (PPAR)/retinoid X receptor (RXR). We recently reported that TBT inhibits cell growth and the ATP content in the human embryonic carcinoma cell line NT2/D1 via a non-genomic pathway involving NAD(+)-dependent isocitrate dehydrogenase (NAD-IDH), which metabolizes isocitrate to α-ketoglutarate. However, the molecular mechanisms by which NAD-IDH mediates TBT toxicity remain unclear. In the present study, we evaluated the effects of TBT on mitochondrial NAD-IDH and energy production. Staining with MitoTracker revealed that nanomolar TBT levels induced mitochondrial fragmentation. TBT also degraded the mitochondrial fusion proteins, mitofusins 1 and 2. Interestingly, apigenin, an inhibitor of NAD-IDH, mimicked the effects of TBT. Incubation with an α-ketoglutarate analogue partially recovered TBT-induced mitochondrial dysfunction, supporting the involvement of NAD-IDH. Our data suggest that nanomolar TBT levels impair mitochondrial quality control via NAD-IDH in NT2/D1 cells. Thus, mitochondrial function in embryonic cells could be used to assess cytotoxicity associated with metal exposure.
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku 158-8501, Japan. kanda@nihs.go.jp.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.forename: Yaichiro
authors.initials: Y
authors.lastname: Kotake
authors.forename: Mizuho
authors.initials: M
authors.lastname: Nakano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D002460:Cell Line; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D052244:Endocrine Disruptors / Q000633:toxicity*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D052244:Endocrine Disruptors; D007656:Ketoglutaric Acids; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D014220:Trialkyltin Compounds; D009243:NAD; C011559:tributyltin; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human