Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites
- University of Utah School of Medicine, United States
- University of California, Los Angeles, United States
- University of Washington, United States
Abstract
Most eukaryotic cells retain a mitochondrial fatty acid synthesis (FASII) pathway whose acyl carrier protein (mACP) and 4-phosphopantetheine (Ppant) prosthetic group provide a soluble scaffold for acyl chain synthesis and biochemically couple FASII activity to mitochondrial electron transport chain (ETC) assembly and Fe-S cluster biogenesis. In contrast, the mitochondrion of Plasmodium falciparum malaria parasites lacks FASII enzymes yet curiously retains a divergent mACP lacking a Ppant group. We report that ligand-dependent knockdown of mACP is lethal to parasites, indicating an essential FASII-independent function. Decyl-ubiquinone rescues parasites temporarily from death, suggesting a dominant dysfunction of the mitochondrial ETC. Biochemical studies reveal that Plasmodium mACP binds and stabilizes the Isd11-Nfs1 complex required for Fe-S cluster biosynthesis, despite lacking the Ppant group required for this association in other eukaryotes, and knockdown of parasite mACP causes loss of Nfs1 and the Rieske Fe-S protein in ETC Complex III. This work reveals that Plasmodium parasites have evolved to decouple mitochondrial Fe-S cluster biogenesis from FASII activity, and this adaptation is a shared metabolic feature of other apicomplexan pathogens, including Toxoplasma and Babesia. This discovery unveils an evolutionary driving force to retain interaction of mitochondrial Fe-S cluster biogenesis with ACP independent of its eponymous function in FASII.
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All data reported or analyzed in this manuscript are available and included in the main and supplemental figures and in the source data files.
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Funding
National Institute of General Medical Sciences (R35GM133764)
- Paul A Sigala
National Institute of General Medical Sciences (R01GM089778)
- James A Wohlschlegel
National Institute of Diabetes and Digestive and Kidney Diseases (U54DK110858)
- Paul A Sigala
Burroughs Wellcome Fund (1011969)
- Paul A Sigala
Pew Charitable Trusts (32099)
- Paul A Sigala
National Institute of General Medical Sciences (T32GM122740)
- Jaime Sepulveda
National Institutes of Health (S10OD018210)
- Paul A Sigala
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Falekun et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites
eLife 10:e71636.
https://doi.org/10.7554/eLife.71636
