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2018 ; 9
(3
): 298
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Ceramide-induced BOK promotes mitochondrial fission in preeclampsia
#MMPMID29463805
Ausman J
; Abbade J
; Ermini L
; Farrell A
; Tagliaferro A
; Post M
; Caniggia I
Cell Death Dis
2018[Feb]; 9
(3
): 298
PMID29463805
show ga
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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