Mechanisms governing organelle segregation in Plasmodium falciparum, the human malaria parasite

Abstract

Malaria remains a significant threat to global health, affecting 282 million individuals globally and resulting in 610,000 deaths in 2024. Disease symptoms arise from the exponential growth of Plasmodium parasites within human red blood cells (RBCs), leading to cyclical fevers and severe anemia. After rapid expansion in the bloodstream, a fraction of these parasites differentiate into transmissible gametocytes. Ingestion of these forms by Anopheles mosquitoes sustains the Plasmodium life cycle, driving ongoing malaria transmission. The deadliest of the human malaria parasites, Plasmodium falciparum, contains two essential endosymbiotic organelles that remain closely linked during the Plasmodium life cycle – the apicoplast, a non-photosynthetic plastid, and the mitochondrion. These organelles are faithfully segregated during asexual replication and form long-lasting connections during gametocytogenesis. However, the biological significance and molecular mechanisms underlying these processes remain largely unknown. The remarkable expansion of Plasmodium parasites in the bloodstream is driven by their ability to produce dozens of progeny per replicative cycle. During this process, Plasmodium parasites must replicate and partition their organelles with high fidelity. In Chapter 2, we characterize the role of a novel cytoskeleton-associated protein, PfOGRE (PF3D7_1435600, for organelle retention), that orchestrates one-per cell segregation of the apicoplast and mitochondrion during P. falciparum asexual replication. Additionally, we identify several putative interacting proteins through PfOGRE immunoprecipitation and mass spectrometry experiments. We describe our findings on one of these putative PfOGRE-interacting proteins, PfMyoF. This work provides a foundation for exploring the cytoskeleton-mediated mechanisms that drive organelle segregation in P. falciparum. A small number of Plasmodium parasites differentiate into male and female gametocytes in preparation for transmission to the mosquito vector. Maturation of these forms is accompanied by extensive morphological remodeling, including the formation of long-lasting contacts between the apicoplast and mitochondrion. In Chapter 3, we define a role for PfOGRE in coordinating apicoplast-mitochondrion interactions during gametocytogenesis. Importantly, PfOGRE provides a promising avenue for exploring the functional significance of apicoplast-mitochondrion interactions during gametocytogenesis. Overall, these findings provide novel insight into the cellular mechanisms governing organelle segregation and apicoplast-mitochondrion interactions in P. falciparum.