F. Silva, M., Douglas, K., Sandalli, S., MacLean, A. E. and Sheiner, L. (2023) Functional and biochemical characterization of the Toxoplasma gondii succinate dehydrogenase complex. PLoS Pathogens, 19(12), e1011867. (doi: 10.1371/journal.ppat.1011867) (PMID:38079448) (PMCID:PMC10735183)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
315334.pdf - Published Version Available under License Creative Commons Attribution. 3MB |
Abstract
The mitochondrial electron transport chain (mETC) is a series of membrane embedded enzymatic complexes critical for energy conversion and mitochondrial metabolism. In commonly studied eukaryotes, including humans and animals, complex II, also known as succinate dehydrogenase (SDH), is an essential four-subunit enzyme that acts as an entry point to the mETC, by harvesting electrons from the TCA cycle. Apicomplexa are pathogenic parasites with significant impact on human and animal health. The phylum includes Toxoplasma gondii which can cause fatal infections in immunocompromised people. Most apicomplexans, including Toxoplasma, rely on their mETC for survival, yet SDH remains largely understudied. Previous studies pointed to a divergent apicomplexan SDH with nine subunits proposed for the Toxoplasma complex, compared to four in humans. While two of the nine are homologs of the well-studied SDHA and B, the other seven have no homologs in SDHs of other systems. Moreover, SDHC and D, that anchor SDH to the membrane and participate in substrate bindings, have no homologs in Apicomplexa. Here, we validated five of the seven proposed subunits as bona fide SDH components and demonstrated their importance for SDH assembly and activity. We further find that all five subunits are important for parasite growth, and that disruption of SDH impairs mitochondrial respiration and results in spontaneous initiation of differentiation into bradyzoites. Finally, we provide evidence that the five subunits are membrane bound, consistent with their potential role in membrane anchoring, and we demonstrate that a DY motif in one of them, SDH10, is essential for complex formation and function. Our study confirms the divergent composition of Toxoplasma SDH compared to human, and starts exploring the role of the lineage-specific subunits in SDH function, paving the way for future mechanistic studies.
| Item Type: | Articles |
|---|---|
| Additional Information: | Our work was funded by research grants from the Medical Research Council MR/W002221/1 to LS and AM, the Wellcome Trust UNS85804 to LS and the Wellcome Trust 221681/Z/20/Z to AM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Douglas, Kiera and Sandalli, Sofia and Ferreira Silva, Miss Mariana and MacLean, Dr Andrew and Sheiner, Professor Lilach |
| Creator Roles: | Ferreira Silva, M.Data curation, Investigation, Methodology, Validation, Visualization, Writing – review and editing Douglas, K.Formal analysis, Investigation Sandalli, S.Formal analysis, Investigation MacLean, A.Conceptualization, Funding acquisition, Investigation, Supervision, Writing – original draft, Writing – review and editing Sheiner, L.Conceptualization, Funding acquisition, Investigation, Supervision, Writing – original draft, Writing – review and editing |
| Authors: | F. Silva, M., Douglas, K., Sandalli, S., MacLean, A. E., and Sheiner, L. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | PLoS Pathogens |
| Publisher: | Public Library of Science |
| ISSN: | 1553-7366 |
| ISSN (Online): | 1553-7374 |
| Copyright Holders: | Copyright © 2023 Silva et al. |
| First Published: | First published in PLoS Pathogens 19(12):e1011867 |
| Publisher Policy: | Reproduced under a Creative Commons license |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information