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Toxicology. 2017 May 1;382:108-116. doi: 10.1016/j.tox.2017.03.011. Epub 2017 Mar 10.

Mitochondrial toxicity of perfluorooctane sulfonate in mouse embryonic stem cell-derived cardiomyocytes.

Author information

1
Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China; Department of Pharmacy, Xiaoshan Hospital, Hangzhou 311200, China.
2
Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
3
Undergraduate Students in Research Training Project at Zhejiang University, Hangzhou 310058, China.
4
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.
5
Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. Electronic address: zdyzxb@zju.edu.cn.

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+]c transient 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+]mito transient 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.

KEYWORDS:

Ca(2+); Embryonic stem cell-derived cardiomyocytes (ESC-CMs); Mitochondria; Perfluorooctane sulfonate (PFOS); Rictor

PMID:
28288859
DOI:
10.1016/j.tox.2017.03.011
[Indexed for MEDLINE]

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