Vitamin E deficiency disrupts molecular pathways of energy metabolism in zebrafish embryos

Embryonic vitamin E (VitE) deficiency causes fetal death in humans, rodents and zebrafish, but the molecular mechanisms still remain unknown. Based on our previous investigations using lipidomics and metabolomics approaches in zebrafish, embryonic VitE deficiency results in increased lipid peroxidation, glucose and choline depletion, metabolic reprogramming and disruption of cellular energy metabolism, which collectively result in lethal outcomes. The mammalian target of rapamycin complex 1 (mTORC1) is a key player of the embryonic nutrient-sensing network. mTORC1 is central to a phosphorylation cascade that is redox sensitive via cysteine oxidation. mTORC1 is dependent upon upstream insulin/IGF-1 signaling, AKT kinases and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a), which collectively integrate signals to affect a range of cellular responses. To test the hypothesis that mTORC1 is dysregulated with VitE deficiency, embryos were obtained by spawning adult 5D zebrafish fed defined diets with (E+) or without (E—) for >80 days. Embryos were collected at 24 hours-post-fertilization, RNA extracted and relative gene expression of targets associated with energy metabolism and autophagy evaluated by RT-qPCR. The expression profiling of several members of the mTORC1 signaling pathways in E— embryos were altered including: the serine/threonine kinase (akt3a) involved in cell survival and proliferation; the transcription factor eb (tfeb) involved in lysosomal biogenesis; and the autophagy related 5 (atg5) involved in mitophagy. These alterations suggest modified energy regulation in the VitE-deficient embryos and further support the involvement of mTOR associated-pathways. Data from these studies provide a foundation for further exploration into VitE’s role in developmental energy metabolism.