McDougall Melissa, Choi Jaewoo, Kim Hye-Kyeong, Bobe Gerd, Stevens J Frederik, Cadenas Enrique, Tanguay Robert, Traber Maret G
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; College of Public Health and Human Sciences, Oregon State University, Corvallis, OR 97331, USA.
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Free Radic Biol Med. 2017 Mar;104:324-332. doi: 10.1016/j.freeradbiomed.2017.01.020. Epub 2017 Jan 14.
Vitamin E (α-tocopherol, VitE) was discovered in 1922 for its role in preventing embryonic mortality. We investigated the underlying mechanisms causing lethality using targeted metabolomics analyses of zebrafish VitE-deficient embryos over five days of development, which coincided with their increased morbidity and mortality. VitE deficiency resulted in peroxidation of docosahexaenoic acid (DHA), depleting DHA-containing phospholipids, especially phosphatidylcholine, which also caused choline depletion. This increased lipid peroxidation also increased NADPH oxidation, which depleted glucose by shunting it to the pentose phosphate pathway. VitE deficiency was associated with mitochondrial dysfunction with concomitant impairment of energy homeostasis. The observed morbidity and mortality outcomes could be attenuated, but not fully reversed, by glucose injection into VitE-deficient embryos at developmental day one. Thus, embryonic VitE deficiency in vertebrates leads to a metabolic reprogramming that adversely affects methyl donor status and cellular energy homeostasis with lethal outcomes.
维生素E（α-生育酚，VitE）于1922年被发现，因其在预防胚胎死亡方面的作用。我们通过对斑马鱼维生素E缺乏胚胎发育的五天进行靶向代谢组学分析，研究了导致致死的潜在机制，这与它们发病率和死亡率的增加相吻合。维生素E缺乏导致二十二碳六烯酸（DHA）过氧化，消耗含DHA的磷脂，尤其是磷脂酰胆碱，这也导致胆碱消耗。这种脂质过氧化增加也增加了NADPH氧化，通过将葡萄糖分流到磷酸戊糖途径而使其消耗。维生素E缺乏与线粒体功能障碍相关，同时能量稳态受损。在发育第一天向维生素E缺乏的胚胎注射葡萄糖，可以减轻但不能完全逆转观察到的发病率和死亡率结果。因此，脊椎动物胚胎维生素E缺乏会导致代谢重编程，对甲基供体状态和细胞能量稳态产生不利影响，并导致致命后果。
