Ceramide-induced BOK promotes mitochondrial fission in preeclampsia

被引:83
作者
Ausman, Jonathan [1 ,2 ]
Abbade, Joelcio [1 ,3 ]
Ermini, Leonardo [1 ]
Farrell, Abby [1 ,2 ]
Tagliaferro, Andrea [1 ]
Post, Martin [2 ,4 ,5 ]
Caniggia, Isabella [1 ,2 ,4 ,6 ]
机构
[1] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5T 1X5, Canada
[2] Univ Toronto, Inst Med Sci, Toronto, ON, Canada
[3] UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept Obstet & Gynecol, Sao Paulo, Brazil
[4] Univ Toronto, Dept Physiol, Toronto, ON, Canada
[5] Hosp Sick Children, Peter Gilgan Ctr Res & Learning, Translat Med Program, Toronto, ON M5G 1X8, Canada
[6] Univ Toronto, Dept Obstet & Gynecol, Toronto, ON, Canada
基金
美国国家卫生研究院;
关键词
TROPHOBLAST CELL-DEATH; FAMILY-MEMBER BOK; ENDOPLASMIC-RETICULUM; PLACENTAL DEVELOPMENT; OXIDATIVE STRESS; PROTEIN DRP1; FUSION; BCL-2; OPA1; DIFFERENTIATION;
D O I
10.1038/s41419-018-0360-0
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mitochondria are in a constant balance of fusing and dividing in response to cellular cues. Fusion creates healthy mitochondria, whereas fission results in removal of non-functional organelles. Changes in mitochondrial dynamics typify several human diseases. However, the contribution of mitochondrial dynamics to preeclampsia, a hypertensive disorder of pregnancy characterized by placental cell autophagy and death, remains unknown. Herein, we show that the mitochondrial dynamic balance in preeclamptic placentae is tilted toward fission (increased DRP1 expression/activation and decreased OPA1 expression). Increased phosphorylation of DRP1 (p-DRP1) in mitochondrial isolates from preeclamptic placentae and transmission electron microscopy corroborated augmented mitochondrial fragmentation in cytotrophoblast cells of PE placentae. Increased fission was accompanied by build-up of ceramides (CERs) in mitochondria from preeclamptic placentae relative to controls. Treatment of human choriocarcinoma JEG3 cells and primary isolated cytrophoblast cells with CER 16:0 enhanced mitochondrial fission. Loss-and gain-of-function experiments showed that Bcl-2 member BOK, whose expression is increased by CER, positively regulated p-DRP1/DRP1 and MFN2 expression, and localized mitochondrial fission events to the ER/MAM compartments. We also identified that the BH3 and transmembrane domains of BOK were vital for BOK regulation of fission. Moreover, we found that full-length PTEN-induced putative kinase 1 (PINK1) and Parkin, were elevated in mitochondria from PE placentae, implicating mitophagy as the process that degrades excess mitochondria fragments produced from CER/BOK-induced fission in preeclampsia. In summary, our study uncovered a novel CER/BOK-induced regulation of mitochondrial fission and its functional consequence for heightened trophoblast cell autophagy in preeclampsia.
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页数:18
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