mACP

mACP (PF3D7_1208300) is a divergent mitochondrial acyl carrier protein in Plasmodium falciparum that has been repurposed away from fatty acid synthesis to serve an essential role in mitochondrial Fe-S cluster biogenesis (PMID:34612205). Unlike canonical eukaryotic mitochondrial ACPs, mACP lacks the 4-phosphopantetheine (Ppant) prosthetic group, decoupling it from FASII activity, yet it still directly binds and stabilizes the Isd11-Nfs1 cysteine desulfurase complex that initiates Fe-S cluster assembly (PMID:34612205). Conditional knockdown of mACP is lethal and causes secondary loss of Nfs1 and of the Rieske Fe-S protein of ETC complex III, producing a dominant defect in the mitochondrial electron transport chain that is transiently rescued by decyl-ubiquinone (PMID:34612205). Beyond this Fe-S biogenesis and ETC-stabilization role, no additional mechanistic function of mACP has been characterized in the available corpus.

1. 2021 High

   It was unknown whether the mitochondrial ACP of P. falciparum had an essential role independent of fatty acid synthesis; conditional knockdown established that mACP is essential and that its loss primarily disables the mitochondrial ETC.

   Evidence Ligand-dependent conditional knockdown with viability assay and chemical rescue by decyl-ubiquinone

   PMID:34612205

   Open questions at the time

   • Does not identify the direct molecular target whose loss disables the ETC
   • Transient nature of decyl-ubiquinone rescue not mechanistically resolved
2. 2021 High

   The molecular basis of mACP essentiality was unresolved; binding and knockdown studies showed mACP physically stabilizes the Isd11-Nfs1 Fe-S biogenesis complex and that its depletion causes loss of Nfs1 and the Rieske Fe-S protein, defining a Fe-S biogenesis-to-complex III pathway.

   Evidence Biochemical pulldown/binding studies plus conditional knockdown with immunoblot for Nfs1 and Rieske Fe-S protein

   PMID:34612205

   Open questions at the time

   • Structural basis of Ppant-independent Isd11-Nfs1 binding not resolved
   • Whether mACP participates in other Fe-S client maturation steps unknown
3. 2021 Medium

   Whether mACP retained the canonical ACP prosthetic group was unclear; biochemical characterization established that mACP lacks the 4-phosphopantetheine group, explaining its decoupling from FASII and its divergence from canonical mitochondrial ACPs.

   Evidence Sequence and biochemical characterization of the absence of the Ppant group

   PMID:34612205

   Open questions at the time

   • Single-lab biochemical assignment
   • Structural consequences of Ppant absence for the Isd11-Nfs1 interface not defined
4. 2024 Low

   mACP's subcellular assignment was tested indirectly when it served as an HA-tagged mitochondrial negative control in an apicoplast interactor screen, confirming its mitochondrial residence and that it does not co-purify with apicoplast proteins.

   Evidence Anti-HA immunoprecipitation with tandem mass spectrometry, using mACP as a negative control

   PMID:39660822

   Open questions at the time

   • mACP was not the subject of study, only a control
   • No new mACP-specific interactors defined
5. 2024 Low

   The proposed mACP-to-Rieske epistatic pathway gained indirect support when conditional depletion of the Rieske Fe-S protein reproduced the loss of PfRieske consistent with the pathway placing mACP upstream of complex III Fe-S maturation.

   Evidence Conditional knockdown of PfRieske with immunoblot, interpreted in the context of prior mACP work

   PMID:39273187

   Open questions at the time

   • No direct experimentation on mACP in this study
   • Epistasis inferred from citation rather than co-perturbation

• How mACP mechanistically substitutes for the Ppant-dependent ACP contacts of canonical eukaryotes to stabilize Isd11-Nfs1, and whether it has any Fe-S client roles beyond the Rieske protein, remain unresolved.
• No structure of the mACP-Isd11-Nfs1 interface
• Full set of Fe-S clients downstream of mACP unknown
• Mechanism of ETC dominance upon mACP loss not fully defined