Evidence for a role of hemozoin in metabolism and gametocytogenesis

Hemozoin is generally considered a waste deposit that is formed for the sole purpose of detoxification of free heme that results from the digestion of hemoglobin by Plasmodium parasites. However, several observations of parasite multiplication, both in vertebrate and invertebrate hosts are suggestive of a wider, but overlooked, metabolic role for this product. The presence of clinical peripheral blood samples of P. falciparum with high parasitemia containing only hemozoin-deficient (non-pigmented) asexual forms has been repeatedly confirmed. Such samples stand in contrast with other samples that contain mostly pigmented circulating trophozoites and gametocytes, indicating that pigment accumulation is a prominent feature of gametocytogenesis. The restricted size, i.e. below detection by light microscopy, of hemozoin in asexual merozoites and ringforms of P. falciparum implies its continuous turnover, supporting a role in metabolism. The prominent interaction of hemozoin with several antimalarial drugs, the involvement of proteins in hemozoin formation, and the finding of plasmodial genes coding for a hemeoxygenase-like protein argue for a wider and more active role for hemozoin in the parasite’s metabolism. The observed association of hemozoin with crystalloids during ookinete development is consistent with a useful function to it during parasite multiplication in the invertebrate host. Finally, alternative mechanisms, other than hemozoin formation, provide substitute or additional routes for heme detoxification.