The transcription factor XBP1 regulates mitochondrial remodel in spontaneous abortion

Background: Spontaneous abortion (SA) is a clinical dilemma during early pregnancy. It has reported that endoplasmic reticulum stress (ERS) was associated with increased incidence of SA. However, the underlying mechanism remains to be elucidated. Results: : ERS related proteins, including GRP78, p-eIF2a, CHOP and XBP1s, were increased in DSCs under endoplasmic reticulum stress (ERS-DSCs). Meanwhile, the inflammatory cytokines and apoptosis were revealed to be enhanced in ERS-DSCs. Interestingly, loss of XBP1 reduced the inflammatory cytokines and apoptosis in ERS-DSCs. Mechanismly, XBP1s coupled with the promoter of a ubiquitin E3 ligase tumour necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 expression was suppressed in ERS-DSCs post treatment with shXBP1, which was accompanied by mitochondrial dysfunction and apoptosis. TRAF6 induced mitochondrial dysfunction in ERS-DSCs by suppressing the mammalian target of rapamycin complex 2 (mTORC2), thereby enhancing ROS levels, mitochondrial dysfunction, and apoptosis. Moreover, Overexpression of mTORC2 abrogated TRAF6-induced ROS, mitochondrial dysfunction, and apoptosis, which involved in the activation of Akt/FoxO1 signaling. Conclusions: : Theses resuluts demonstrated that Loss of XBP1 mediated mitochondrial remodel by regulating TRAF6/mTORC2 signaling pathway plays a critical role in the preservation of DSCs during early pregnancy, which provides novel insights into the pathological mechanism of SA and potential therapeutic targets for SA.