Unstable Hemoglobins: The Role of Heme Loss in Heinz Body Formation

Mutant, unstable hemoglobins precipitate as Heinz bodies in circulating red blood cells resulting in their premature hemolysis. We stress that generally these hemoglobins contain amino acid substitutions in the beta-chain of globin near the heme pocket, and demonstrate that heme binding suffers thereby. Four genetically unstable hemoglobins lost roughly half their heme content while precipitating into Heinz bodies. Conversely, repletion of hemes in vitro corrected the characteristically aberrant electrophoretic mobilities of these hemoglobins and concomitantly prevented their excessive denaturation into Heinz bodies. From the finding that heme-containing alpha-chains accumulate in solution during Heinz body formation, we propose that heme loss occurs predominantly from mutant beta-chains, which then precipitate. This mechanism of Heinz body formation is valid in most, but not all, the unstable hemoglobinopathies.