Iron and selenium: At the crossroads of development and death in oligodendrocytes.

Myelination is a critical neurodevelopmental process where nerve fibers are encased with the lipid-rich, insulating substance known as myelin. It is essential for proper function of the nervous system, as myelin enhances the fidelity and speed of nerve conduction, while also providing a protective barrier. The early postnatal period represents the most rapid phase of myelination, where numbers of mature oligodendrocytes peak. Oligodendrocyte maturation is an energetically demanding process that involves increased iron uptake, heightened metabolism, and elevated production of antioxidants. It is critically dependent upon thyroid hormone signaling and increased synthesis of plasmenyl-phosphatidylethanolamine (PE; aka plasmalogen), a subclass of phospholipids that is particularly abundant in the brain. Plasmenyl-PE is characterized by a vinyl-ether bond that preferentially reacts with oxidants, thereby protecting against lipid peroxidation. Notably, thyroid hormone metabolism and plasmenyl-PE synthesis both require selenoproteins, a clade of proteins containing the 21st amino acid, selenocysteine. Selenoproteins also constitute key regulators of redox tone, with glutathione peroxidase 4 recognized as the master regulator of ferroptosis, a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. This review aims to illuminate the delicate balance between iron homeostasis, lipid metabolism, thyroid hormone signaling, and selenoprotein synthesis in oligodendrocytes. This interconnected relationship is of paramount importance for neurodevelopment, as mutations in many genes mediating these processes converge on a phenotype characterized by hypomyelination, cognitive impairment, neurodegeneration, and motor deficits.