Divergent Acyl Carrier Protein Mediates Mitochondrial Fe-S Cluster Biosynthesis in Malaria Parasites

Plasmodium falciparum malaria parasites are early-diverging eukaryotes with many unusual metabolic adaptations. Understanding these adaptations will give insight into parasite evolution and unveil new parasite-specific drug targets. In contrast to human cells, the Plasmodium mitochondrion lacks type II fatty acid biosynthesis (FASII) enzymes yet curiously retains a divergent acyl carrier protein (mACP) incapable of modification by a 4-phosphopantetheine (Ppant) group required for canonical ACP function as the scaffold for fatty acid synthesis. We report that ligand-dependent knockdown of mACP expression is lethal to parasites, indicating an essential FASII-independent function. Decyl-ubiquinone rescues parasites temporarily from this lethal phenotype, suggesting a dominant dysfunction of the mitochondrial electron transport chain (ETC) followed by broader defects beyond the ETC. Biochemical studies reveal that Plasmodium mACP binds and stabilizes the Isd11-Nfs1 cysteine desulfurase complex required for Fe-S cluster biosynthesis, and mACP knockdown causes loss of both Nfs1 and the Rieske Fe-S cluster protein in ETC Complex III. This work identifies Ppant-independent mACP as an essential mitochondrial adaptation in Plasmodium malaria parasites that appears to be a shared metabolic feature of Apicomplexan pathogens, including Toxoplasma and Babesia. This parasite-specific adaptation highlights the ancient, fundamental role of ACP in mitochondrial Fe-S cluster biogenesis and reveals an evolutionary driving force to retain this interaction with ACP independent of its eponymous function in fatty acid synthesis.