title: Mitochondrial toxicity of perfluorooctane sulfonate in mouse embryonic stem cell-derived cardiomyocytes.
abstract: Perfluorooctane sulfonate (PFOS) is a persistent organic contaminant that may cause cardiotoxicity in animals and humans. However, little is known about the underlying mechanism by which it affects the organelle toxicity in cardiomyocytes during the cardiogenesis. Our previous proteomic study showed that differences of protein expression mainly existed in mitochondria of cardiomyocytes differentiated from embryonic stem (ES) cells after exposure to PFOS. Here, we focused on mitochondrial toxicity of PFOS in ES cell-derived cardiomyocytes. The cardiomyogenesis from ES cells in vitro was inhibited, and the expression of L-type Ca2+channel (LTCC) was decreased to interrupt [Ca2+]ctransient amplitude in cardiomyocytes after PFOS treatment. Transmission electron microscope revealed that swollen mitochondrion with vacuole in PFOS-treated cells. Meanwhile, mitochondrial transmembrane potential (ΔΨm) was declined and ATP production was lowered. These changes were related to the increased EGFR phosphorylation, activated Rictor signaling, then mediated HK2 binding to mitochondrial membrane. Furthermore, PFOS reduced the interaction of IP3R-Grp75-VDAC and accumulated intracellular fatty acids by activating Rictor, thereby attenuating PGC-1α and Mfn2 expressions, then destroying mitochondria-associated endoplasmic reticulum membrane (MAM), which resulted in the decrease of [Ca2+]mitotransient amplitude triggered by ATP. In conclusion, mitochondrial structure damages and abnormal Ca2+shuttle were the important aspects in PFOS-induced cardiomyocytes toxicity from ES cells by activating Rictor signaling pathway.
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China; Department of Pharmacy, Xiaoshan Hospital, Hangzhou 311200, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Tang
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Jia-Dan
authors.initials: JD
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Xu
authors.affiliation: Undergraduate Students in Research Training Project at Zhejiang University, Hangzhou 310058, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Undergraduate Students in Research Training Project at Zhejiang University, Hangzhou 310058, China.
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Zheng
authors.affiliation: The Population Council at the Rockefeller University, New York, NY 10021, USA; Institute of Reproductive Biomedicine, The 2nd Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China.
authors.forename: Ren-Shan
authors.initials: RS
authors.lastname: Ge
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. Electronic address: zdyzxb@zju.edu.cn.
authors.forename: Dan-Yan
authors.initials: DY
authors.lastname: Zhu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D066246:ErbB Receptors / Q000378:metabolism; D005466:Fluorocarbons / Q000633:toxicity*; D019344:Lactic Acid / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology*; D046912:Multiprotein Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D017738:Alkanesulfonic Acids; D002352:Carrier Proteins; D004785:Environmental Pollutants; D005466:Fluorocarbons; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C076994:perfluorooctane sulfonic acid; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D002118:Calcium
keywords: Ca(2+); Embryonic stem cell-derived cardiomyocytes (ESC-CMs); Mitochondria; Perfluorooctane sulfonate (PFOS); Rictor