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Lookup NU author(s): Dr Kacper Sendra, Andrew WatsonORCiD, Ekaterina Kozhevnikova, Emeritus Professor T. Martin Embley FMedSci FRSORCiD, Professor Robert HirtORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Mitosomes are highly reduced forms of mitochondria which have lost two of the ‘defining’ features of the canonical organelle, the mitochondrial genome, and the capacity to generate energy in the form of ATP. Mitosomes are found in anaerobic protists and obligate parasites and, in most of the studied organisms, have a conserved function in the biosynthesis of iron-sulfur clusters (ISC) that are indispensable cofactors of many essential proteins. The genomes of some mitosome-bearing human pathogenic Microsporidia encode homologues of an alternative oxidase (AOX). This mitochondrial terminal respiratory oxidase is absent from the human host, and hence is a potential target for the development of new antimicrobial agents. Here we present experimental evidence for the mitosomal localization of AOX in the microsporidian Trachipleistophora hominis and demonstrate that it has an important role during the parasite’s life cycle progression. Using a recently published methodology for synchronising T. hominis infection of mammalian cell lines, we demonstrated specific inhibition of T. hominis early meront growth and replication by an AOX inhibitor colletochlorin B. Treatment of T. hominis-infected host cells with the drug also inhibited re-infection by newly formed dispersive spores. Addition of the drug during the later stages of the parasite life cycle, when our methods suggest that AOX is not actively produced and T. hominis mitosomes are mainly active in Fe/S cluster biosynthesis, had no inhibitory effects on the parasites. Control experiments with the AOX-deficient microsporidian species Encephalitozoon cuniculi, further demonstrated the specificity of inhibition by the drug. Using the same methodology, we demonstrate effects of two clinically used anti-microsporidian drugs albendazole and fumagillin on the cell biology and life cycle progression of T. hominis infecting mammalian host cells. In summary, our results reveal that T. hominis mitosomes have an active role to play in the progression of the parasite life cycle as well as an important role in the biosynthesis of essential Fe/S clusters. Our work also demonstrates that T. hominis is a useful model for testing the efficacy of therapeutic agents and for studying the physiology and cell biology of microsporidian parasites growing inside infected mammalian cells.
Author(s): Sendra KM, Watson AK, Kozhevnikova E, Moore AL, Embley TM, Hirt RP
Publication type: Article
Publication status: Published
Journal: PLoS Pathogens
Year: 2022
Volume: 18
Issue: 12
Online publication date: 20/12/2022
Acceptance date: 24/11/2022
Date deposited: 23/12/2022
ISSN (print): 1553-7366
ISSN (electronic): 1553-7374
Publisher: Public Library of Science
URL: https://doi.org/10.1371/journal.ppat.1011024
DOI: 10.1371/journal.ppat.1011024
PubMed id: 36538568
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