Lethal dysregulation of energy metabolism during embryonic vitamin E deficiency

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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.HIGHLIGHTSVitamin E deficiency depletes phosphatidylcholine, choline and methyl donors.Increased lipid peroxidation shunts glucose to the pentose phosphate pathway.Vitamin E deficiency causes mitochondrial dysfunction impairing energy homeostasis.Outcomes could be attenuated by glucose injection into deficient embryos.Vitamin E deficiency leads to a metabolic reprogramming that dysregulates cellular energy homeostasis.

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