FIGURE 8.

Schematic of the hemolytic anemia in Nmnat3^gt/gt mice. Nmnat3 is the dominant Nmnat among the three isoforms in mature erythrocytes, and its deficiency leads to a drastic depletion of the NAD pool. A lowered NAD level inhibits glycolysis at GAPDH and reverse the glycolytic flow between Fru-1,6-BP and GAP. Impaired ATP synthesis in Nmnat3^gt/gt erythrocytes leads to the dysfunction of Na⁺,K⁺-ATPase and a resulting spiked shaped erythrocytes, which are preferentially trapped and destroyed by the reticuloendothelial system of the spleen. Thus, Nmnat3 deficiency in mice caused splenomegaly and hemolytic anemia.