Apicomplexan mitoribosome from highly fragmented rRNAs to a functional machine

SUMMARY

The phylum Apicomplexa comprises eukaryotic parasites that cause fatal diseases affecting millions of people and animals worldwide. Their mitochondrial genomes have been significantly reduced, leaving only three protein-coding genes and highly fragmented mitoribosomal rRNAs, raising challenging questions about mitoribosome composition, assembly and structure. This study reveals how Toxoplasma gondii assembles over 40 mt-rRNA fragments using exclusively nuclear-encoded mitoribosomal proteins and three lineage-specific families of RNA-binding proteins. Among these are four proteins from the Apetala2/Ethylene Response Factor (AP2/ERF) family, originally known as transcription factors in plants and Apicomplexa, now repurposed as essential mitoribosome components. Cryo-EM analysis of the mitoribosome structure demonstrates how these AP2 proteins function as RNA binders to maintain mitoribosome integrity. The mitoribosome is also decorated with members of lineage-specific RNA-binding proteins belonging to RAP (RNA-binding domain abundant in Apicomplexa) proteins and HPR (heptatricopeptide repeat) families, highlighting the unique adaptations of these parasites. Solving the molecular puzzle of apicomplexan mitoribosome could inform the development of therapeutic strategies targeting organellar translation.

Full article: https://www.nature.com/articles/s41467-024-55033-z

Why is it important?

Mitochondria, often referred to as the powerhouses of the cell, rely on specialized molecular machines called mitoribosomes to produce proteins essential for energy generation. In a group of parasites called Apicomplexa, including Plasmodium falciparum, which causes malaria, and Toxoplasma gondii, the agent of toxoplasmosis, these mitoribosomes are exceptionally complex and poorly understood. This research uncovered a surprising discovery: four proteins, traditionally known as transcription factors (ApiAP2s), were found in T. gondii as essential components of its mitoribosome. These mitochondrial AP2s (mtAP2s), instead of binding DNA as expected, take on a completely new role in T. gondii. They assemble highly fragmented pieces of ribosomal RNAs into a functional mitoribosome. Without these proteins, critical components of the mitochondrial energy machinery, Complexes III and IV, fail to form, crippling energy production.  Using advanced imaging techniques (CryoEM), the authors revealed that the T. gondii mitoribosome consists of over 120 proteins and more than 40 fragmented RNA pieces, making it far more complex than those found in other organisms. The mtAP2 proteins act as RNA-binding anchors, stitching together fragmented rRNAs to create a functional translation machine to ensure normal mitochondrial function.

These findings shed light on how T. gondii mitoribosome is assembled, providing insights into its distinctive biology and presenting potential new avenues for targeting the energy centers of these parasites to treat serious human diseases like toxoplasmosis and malaria.

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