Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/71636 |
| _version_ | 1811201434899709952 |
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| author | Seyi Falekun Jaime Sepulveda Yasaman Jami-Alahmadi Hahnbeom Park James A Wohlschlegel Paul A Sigala |
| author_facet | Seyi Falekun Jaime Sepulveda Yasaman Jami-Alahmadi Hahnbeom Park James A Wohlschlegel Paul A Sigala |
| author_sort | Seyi Falekun |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:21:40Z |
| format | Article |
| id | doaj.art-e26ae9a9b2774268824fb1a004ffa0c3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:21:40Z |
| publishDate | 2021-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e26ae9a9b2774268824fb1a004ffa0c32022-12-22T03:52:07ZengeLife Sciences Publications LtdeLife2050-084X2021-10-011010.7554/eLife.71636Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasitesSeyi Falekun0https://orcid.org/0000-0003-2280-4424Jaime Sepulveda1https://orcid.org/0000-0002-3557-4093Yasaman Jami-Alahmadi2Hahnbeom Park3James A Wohlschlegel4Paul A Sigala5https://orcid.org/0000-0002-3464-3042Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United StatesDepartment of Biochemistry, University of Utah School of Medicine, Salt Lake City, United StatesDepartment of Biological Chemistry, University of California, Los Angeles, Los Angeles, United StatesDepartment of Biochemistry, University of Washington, Seattle, United StatesDepartment of Biological Chemistry, University of California, Los Angeles, Los Angeles, United StatesDepartment of Biochemistry, University of Utah School of Medicine, Salt Lake City, United StatesMost 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.https://elifesciences.org/articles/71636malariaorganelle adaptationmitochondriaacyl carrier proteinFe-S cluster synthesis |
| spellingShingle | Seyi Falekun Jaime Sepulveda Yasaman Jami-Alahmadi Hahnbeom Park James A Wohlschlegel Paul A Sigala Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites eLife malaria organelle adaptation mitochondria acyl carrier protein Fe-S cluster synthesis |
| title | Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites |
| title_full | Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites |
| title_fullStr | Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites |
| title_full_unstemmed | Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites |
| title_short | Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites |
| title_sort | divergent acyl carrier protein decouples mitochondrial fe s cluster biogenesis from fatty acid synthesis in malaria parasites |
| topic | malaria organelle adaptation mitochondria acyl carrier protein Fe-S cluster synthesis |
| url | https://elifesciences.org/articles/71636 |
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