A dynamic barrier: remodeling of the nuclear envelope during closed mitosis in malaria parasites

Abstract

Plasmodium falciparum, the protozoan parasite responsible for the most severe form of human malaria, replicates through an unconventional mode of closed mitosis, where the nuclear envelope (NE) remains intact across multiple asynchronous nuclear divisions. This Full Circle minireview illustrates how a decade-long journey-from early electron microscopy observations of nuclear pore dynamics-has evolved into a broader investigation of NE composition, architecture, and regulation across the parasite life cycle. Advances in imaging, including ultrastructure expansion microscopy and cryo-electron tomography, revealed key features such as the bipartite microtubule organizing center, nuclear pore complex rosettes, and specialized NE scaffolds. Structure-guided and proteomic approaches identified divergent SUN-domain proteins, PfSUN1 and PfSUN2, as essential for NE integrity, genome stability, and chromatin positioning during schizogony. Hi-C analyses further uncovered species- and stage-specific chromatin organization, linking peripheral heterochromatin clustering to virulence gene regulation and life cycle progression. Despite lacking lamins, Plasmodium's NE functions as a dynamic architectural hub that bridges chromatin, spindle microtubules, and organelle inheritance. Open questions remain about the full NE proteome, organelle-NE contact sites, and the possibility that mechanical deformation of the nucleus during red blood cell invasion could influence gene expression. These insights not only redefine Plasmodium cell biology but also position NE-associated components as attractive therapeutic targets. By coupling methodological innovation with conceptual inquiry, the study of NE dynamics in Plasmodium offers a powerful model for uncovering general principles of nuclear organization and adaptation in divergent eukaryotes.

Keywords: Plasmodium falciparum; apicomplexan parasites; closed mitosis; nuclear envelope dynamics; nuclear pore complex; ultrastructure expansion microscopy.

Fig 1

Divergent modes of mitosis and the centriolar plaque (CP) architecture in Plasmodium. (a) Comparison between mammalian open mitosis (left) and Plasmodium falciparum closed mitosis (right) during blood-stage replication (schizogony). P. falciparum is a haploid protozoan that undergoes asexual replication in human red blood cells through a unique process involving multiple rounds of nuclear division without immediate cytokinesis. (1) In open mitosis, the nuclear envelope breaks down, allowing cytoplasmic spindle microtubules to interact with kinetochores. In contrast, Plasmodium undergoes closed mitosis, with the nuclear envelope intact and spindle microtubules nucleated from the intranuclear side of the CP. (2) Chromosomes align at the metaphase plate in both systems; however, in Plasmodium, this occurs within an intact nucleus and involves 14 chromosomes that remain largely uncondensed throughout mitosis, never adopting the canonical X-shaped morphology observed in higher eukaryotes. (3) Anaphase and chromosome segregation proceed via nuclear microtubules. (4) Unlike higher eukaryotic cells that undergo a single round of synchronized mitosis followed by cytokinesis, Plasmodium blood-stage parasites undergo multiple rounds of asynchronous nuclear division within a shared cytoplasm. This results in a multinucleated schizont. Final daughter cell formation occurs through segmentation, a specialized cytokinesis process requiring the assembly of a dynamic multiprotein structure known as the basal complex. (b) Schematic of the Plasmodium CP, a bipartite microtubule-organizing center embedded in the nuclear envelope. The CP consists of an extranuclear outer domain (containing proteins such as Sfi1 and centrins) and an intranuclear inner domain (where γ-tubulin nucleates spindle microtubules). These microtubules connect to kinetochores via the NDC80 complex (including SPC25 and NUF2) to mediate chromosome segregation. Unlike canonical centrosomes, CPs lack centrioles and instead present a distinct architecture, comprising inner, core, and outer domains. Centromeres (orange) and telomeres (green) associate with the nuclear periphery, while chromatin remains uncondensed throughout mitosis.

Fig 2

Nuclear envelope (NE) organization and nuclear pore complex (NPC) architecture in asexual Plasmodium blood-stage parasites. (a) Schematic overview of a P. falciparum parasite upon entry into mitosis and cell division (schizogony) within the human red blood cell. The parasite contains a single nucleus surrounded by a NE, which houses the bipartite centriolar plaque (CP) and hundreds of NPCs. NPC biogenesis occurs upon mitosis, and the newly formed pores are distributed among daughter nuclei following each nuclear division. NPCs are not evenly spaced but form a distinctive rosette-like cluster around the CP, a spatial organization that is maintained throughout mitosis. In the cytoplasm, the endoplasmic reticulum (ER), Golgi apparatus, and food vacuole (site of hemoglobin digestion). Young parasites (ring; early trophozoites) contain a single mitochondrion and a non-photosynthetic plastid organelle called the apicoplast, both of which possess their own genome. (b) Model of the P. falciparum NPC, showing individual nucleoporins (Nups) organized into cytoplasmic filaments, outer ring, FG-repeat-containing channel proteins, and inner ring components. Nups shown in light gray-colored boxes are experimentally supported, while those in blue boxes are predicted by BLAST homology. The presence of a nuclear basket remains uncertain; in the related apicomplexan T. gondii, cryo-electron tomography (cryoET) has revealed that a canonical nuclear basket is absent, raising the possibility that Plasmodium may share this architectural feature. (c) Zoomed-in view of the NE in P. falciparum, illustrating multiple NPCs embedded in the NE and their spatial proximity to the CP. Both experimentally supported and BLAST-predicted NE-associated proteins are depicted, with consistent color-coding. SUN-domain proteins (SUN1 and SUN2) are shown to bridge the NE, potentially linking chromatin to the nuclear periphery. Transmembrane proteins such as Ssm4 and Slp1 may contribute to NE architecture or chromatin anchoring. Notably, Plasmodium lacks a nuclear lamina, a scaffold structure found in many eukaryotes, which may influence how chromatin is tethered to the NE and how nuclear integrity is maintained during closed mitosis. NPCs remain clustered near the CP, underscoring a potential functional connection between nuclear transport, mitotic microtubule organization, and chromosome segregation.