Oligodendrocyte Slc48a1 (Hrg1) encodes a functional heme transporter required for myelin integrity

Oligodendrocytes (OLs) of the central nervous system require iron for proteolipid biosynthesis during the myelination process. Although most heme is found complexed to hemoglobin in red blood cells, surprisingly, we found that Slc48a1, encoding the heme transporter Hrg1, is expressed at higher levels in OLs than any other cell type in rodent and humans. We confirmed in situ that Hrg1 is expressed in OLs but not their precursors (OPCs) and found that Hrg1 proteins in CNS white matter co‐localized within myelin sheaths. In older Hrg1 null mutant mice we observed reduced expression of myelin associated glycoprotein (Mag) and ultrastructural myelin defects reminiscent of Mag‐null animals, suggesting myelin adhesion deficiency. Further, we confirmed reduced myelin iron levels in Hrg1 null animals in vivo, and show that OLs in vitro can directly import both the fluorescent heme analogue ZnMP and heme itself, which rescued iron deficiency induced inhibition of OL differentiation in a heme‐oxidase‐dependent manner. Together these findings indicate OL Hrg1 encodes a functional heme transporter required for myelin integrity. Main Points Hrg1 is a heme transporter in myelin. Heme is an auxiliary source of iron for oligodendrocytes and required for Mag expression. Hrg1 KO mice have increased periaxonal space due to decreased levels of Mag.