Abstract
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.
Highlights
Mitochondria are critical organelles that provide energy through oxidative phosphorylation[1] and coordinate cell death via intrinsic apoptosis[2]
Western blot (WB) revealed a significant increase in OMA-1 content in mitochondrial isolates (MIs) from PE compared with preterm controls (PTCs) (Fig. 1d), indicating that reduced OPA1 levels could be due to increased OMA-1 activity in the inner mitochondrial membrane (IMM)
We show that CERs play a critical role in mitochondrial fission via a mechanism that involves Bcl-2-related ovarian killer (BOK), a pro-apoptotic member of the Bcl-2 family
Summary
Mitochondria are critical organelles that provide energy through oxidative phosphorylation[1] and coordinate cell death via intrinsic apoptosis[2]. Ausman et al Cell Death and Disease (2018)9:298 modification events, most importantly phosphorylation of DRP1 (p-DRP1) at specific serine residue 616 leads to its activation and recruitment to the OMM where it interacts with resident proteins such as mitochondrial fission factor (MFF). This is followed by p-DRP1 oligomerization[8] and consequent hydrolysis of GTP by active DRP1 providing the mechanic–enzymatic force by which fission occurs[9]. In addition to its role in mitochondrial fusion, MFN2 plays a role in fission as this protein tethers together the mitochondria and endoplasmic reticulum (ER) forming the MAM11
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