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.
Highlights
Using conditional knockdown and immunoprecipitation studies, we discovered that mACP is essential for parasite viability and plays a critical role in binding and stabilizing the Isd11-Nfs1 cysteine desulfurase complex required for mitochondrial Fe-S cluster biogenesis
Multiple metabolic pathways operate within the mitochondrion (3), but many are dispensable for blood-stage parasites, and few essential blood-stage functions beyond dihydroorotate dehydrogenase (DHOD) and electron transport chain (ETC) complexes III and IV
Iron-sulfur cluster biosynthesis is an ancient, essential mitochondrial function that has been well studied in yeast and mammalian cells but is sparsely studied in parasites (37)
Summary
Using conditional knockdown and immunoprecipitation studies, we discovered that mACP is essential for parasite viability and plays a critical role in binding and stabilizing the Isd11-Nfs1 cysteine desulfurase complex required for mitochondrial Fe-S cluster biogenesis. Dd2 line expressing mACP-HA2 and Isd11-GFP, we performed reciprocal IP/WB experiments that confirmed stable interaction of these two proteins in parasites
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