Abstract
Endoplasmic reticulum (ER) stress has been implicated in the development of maternal diabetes-induced neural tube defects (NTDs). ER stress-induced C/EBP homologous protein (CHOP) plays an important role in the pro-apoptotic execution pathways. However, the molecular mechanism underlying ER stress- and CHOP-induced neuroepithelium cell apoptosis in diabetic embryopathy is still unclear. Deletion of the Chop gene significantly reduced maternal diabetes-induced NTDs. CHOP deficiency abrogated maternal diabetes-induced mitochondrial dysfunction and neuroepithelium cell apoptosis. Further analysis demonstrated that CHOP repressed the expression of peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α), an essential regulator for mitochondrial biogenesis and function. Both CHOP deficiency in vivo and knockdown in vitro restore high glucose-suppressed PGC-1α expression. In contrast, CHOP overexpression mimicked inhibition of PGC-1α by high glucose. In response to the ER stress inducer tunicamycin, PGC-1α expression was decreased, whereas the ER stress inhibitor 4-phenylbutyric acid blocked high glucose-suppressed PGC-1α expression. Moreover, maternal diabetes in vivo and high glucose in vitro promoted the interaction between CHOP and the PGC-1α transcriptional regulator CCAAT/enhancer binding protein-β (C/EBPβ), and reduced C/EBPβ binding to the PGC-1α promoter leading to markedly decrease in PGC-1α expression. Together, our findings support the hypothesis that maternal diabetes-induced ER stress increases CHOP expression which represses PGC-1α through suppressing the C/EBPβ transcriptional activity, subsequently induces mitochondrial dysfunction and ultimately results in NTDs.