Hemozoin: a waste product after heme detoxification?

Background: Hemozoin is considered a waste byproduct of heme detoxification following hemoglobin digestion; consequently, the biological functions of hemozoin in hemozoin-producing organisms have often been overlooked. However, recent findings indicate that Schistosoma hemozoin facilitates the transfer of iron from erythrocytes to eggs through its formation and degradation, thereby increasing interest in the role of malarial hemozoin.

Methods: Using transmission electron microscopy, we compared the formation of Schistosoma hemozoin and malaria hemozoin. Through transcriptome analysis of different stages of P. falciparum 3D7^WT and P. falciparum 3D7^C580Y,- where the latter serves as a control with reduced hemozoin production, -we analyzed expression patterns of genes related to DNA synthesis, iron, and heme utilization. Using light microscopy, we observed hemozoin aggregation following artemether treatment, and macrophage morphology after ingesting hemozoin in vivo and in vitro.

Results: Similar to Schistosoma hemozoin, malaria hemozoin consists of heme aggregation and a lipid matrix, likely involved in lipid processing and the utilization of heme and iron. Transcriptome analysis reveals that during the trophozoite stage, the expression levels of these genes in P. falciparum 3D7^WT and P. falciparum 3D7C580Y are higher than those during the schizont stage. Correspondingly, less hemozoin was detected at the trophozoite stage, while more was observed during the schizont stage. These results suggest that when more heme and iron are utilized, less heme is available for hemozoin formation. Conversely, when less heme and iron are utilized, they can accumulate for hemozoin formation during the schizont stage, likely benefiting lipid remodeling. Disruption of heme utilization and hemozoin aggregation may lead to parasite death. In addition, the hemozoin released by schizonts can impair macrophage functions, potentially protecting merozoites from phagocytosis. Furthermore, it may be carried by gametocytes into the next host, fulfilling their requirements for iron and heme during their development in mosquitoes.

Conclusions: Hemozoin is not a waste byproduct of heme detoxification but instead plays a crucial role in the parasite's life cycle.