MICMIT

Exploring the fundamental biology of microsporidian mitosomes

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 Obiettivo del progetto (Objective)

'Microsporidia are tiny obligate intracellular parasites of other eukaryotes including patients with HIV/AIDS. Despite their importance, detailed knowledge of the biology of microsporidia is limited. Microsporidia were thought to lack mitochondria but the proposed host laboratory discovered, and have started to functionally characterise, highly reduced remnant mitochondria in these parasites, called mitosomes, which do not make ATP. Mitosomes are vital for parasite survival because they contain key components of the essential pathway for mitochondrial iron-sulphur cluster biosynthesis. However, from published and in- house genome data it appears that the transport proteins that support mitochondrial Fe-S protein biogenesis in model organisms, have been lost by the parasites. These data raise fundamental questions of how mitosomes function and import the substrates they need to produce Fe-S clusters or export the product(s) of this metabolism that (in model organisms) are needed for the biogenesis of essential cytosolic and nuclear Fe-S proteins. In the present proposal I will tackle these questions using a interdisciplinary program combining bioinformatics and organelle proteomics to identify putative mitosome proteins including transporters, molecular cell biology to functionally characterise these proteins, and detailed light and electron microscopy to confirm their localisation. The project will enhance my individual competence and potential for career development through experience of working in a leading UK laboratory with a track record of research training, international collaboration and scientific excellence.'

Introduzione (Teaser)

A European research team studied the biology of human parasites, focusing on novel organelles and their biosynthetic pathways. Apart from fundamental knowledge, these results have commercial exploitation potential as pharmaceutical targets.

Descrizione progetto (Article)

Microsporidia are small intracellular parasites capable of forming spores. They are important human pathogens and are encountered in patients with HIV/AIDS. Despite their medical importance, very little is known about their biology.

Until recently, microsporidia were thought to lack mitochondria. However, remnant mitochondria called mitosomes have been identified in these parasites. These lack ATP but contain components for mitochondrial iron-sulphur cluster biosynthesis.

The scientific objective of the EU-funded 'Exploring the fundamental biology of microsporidian mitosomes' (MICMIT) project was to further study the biology of these organelles. To this end, scientists developed a novel immunocapture- based method for isolating mitosomes from the intracellular parasite Trachipleistophora hominis and the mucosal parasite Giardia lamblia.

Proteomic analyses of the isolated mitosomes identified new candidate mitosomal proteins for both species. Importantly, microsporidian mitosomes from the different species had strong similarities in their functional proteomes indicating an evolutionary conservation of essential components.

Scientists confirmed the presence of the iron-sulphur cluster biosynthesis pathway but discovered differences in the way the different microsporidia exported pathway products. Alongside novel transporter proteins, they also discovered a key player of parasitic DNA and RNA biosynthesis. Instead of producing ATP, the Ynk1 yeast homologue aids the parasite in stealing early substrates from host cells. These are used to carry out interconversions and obtain vital components such as DNA and RNA.

Collectively, the work by the MICMIT study provides fundamental knowledge on the biology of important human parasites. Given the medical importance of microsporidia, the findings of the project could be utilised to develop novel drugs that target one or more of the identified molecules.