Redox-dependent lipoylation of mitochondrial proteins in Plasmodium falciparum

Mol Microbiol. 2014 Oct;94(1):156-71. doi: 10.1111/mmi.12753. Epub 2014 Sep 1.


Lipoate scavenging from the human host is essential for malaria parasite survival. Scavenged lipoate is covalently attached to three parasite proteins: the H-protein and the E2 subunits of branched chain amino acid dehydrogenase (BCDH) and α-ketoglutarate dehydrogenase (KDH). We show mitochondrial localization for the E2 subunits of BCDH and KDH, similar to previously localized H-protein, demonstrating that all three lipoylated proteins reside in the parasite mitochondrion. The lipoate ligase 1, LipL1, has been shown to reside in the mitochondrion and it catalyses the lipoylation of the H-protein; however, we show that LipL1 alone cannot lipoylate BCDH or KDH. A second mitochondrial protein with homology to lipoate ligases, LipL2, does not show ligase activity and is not capable of lipoylating any of the mitochondrial substrates. Instead, BCDH and KDH are lipoylated through a novel mechanism requiring both LipL1 and LipL2. This mechanism is sensitive to redox conditions where BCDH and KDH are exclusively lipoylated under strong reducing conditions in contrast to the H-protein which is preferentially lipoylated under less reducing conditions. Thus, malaria parasites contain two different routes of mitochondrial lipoylation, an arrangement that has not been described for any other organism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Ketoglutarate Dehydrogenase Complex / genetics
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Lipoylation
  • Malaria, Falciparum / parasitology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Oxidation-Reduction
  • Peptide Synthases / genetics
  • Peptide Synthases / metabolism
  • Plasmodium falciparum / chemistry
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / metabolism*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*


  • Mitochondrial Proteins
  • Protozoan Proteins
  • Ketoglutarate Dehydrogenase Complex
  • Peptide Synthases
  • lipoate-protein ligase