Elevation of urinary methylmolonic acid induces the suppression of megalin-mediated endocytotic cycles during vitamin B12 deficiency

Megalin is a scavenger receptor that serves in the endocytosis of a highly diverse group of ligands that includes Vitamin B12. We found an accumulation of megalin closed to apical region in renal proximal tubule cells of Vitamin B12-deficient rats. Interestingly, Vitamin B12 levels also controlled resorption of renal retinol binding protein. Using L2 yolk sac cells, megalin localized to the submembrane compartment by methylmalonic acid (MMA), which accumulates during vitamin B12 deficiency. In addition, MMA inhibited megalin-mediated endocytosis via YWTD repeats motif in an ectodomain of megalin. Therefore, megalin endocytosis may be regulated by MMA.