title: Mitochondrial lipoic acid scavenging is essential for Plasmodium berghei liver stage development.
abstract: Lipoic acid is an essential cofactor for enzymes that participate in key metabolic pathways in most organisms. While in mammalian cells lipoylated proteins reside exclusively in the mitochondria, apicomplexan parasites of the genus Plasmodium harbour two independent lipoylation pathways in the mitochondrion and the apicoplast, a second organelle of endosymbiotic origin. Protein lipoylation in the apicoplast relies on de novo lipoic acid synthesis while lipoylation of proteins in the mitochondrion depends on scavenging of lipoic acid from the host cell. Here, we analyse the impact of lipoic acid scavenging on the development of Plasmodium berghei liver stage parasites. Treatment of P. berghei-infected HepG2 cells with the lipoic acid analogue 8-bromo-octanoic acid (8-BOA) abolished lipoylation of mitochondrial enzyme complexes in the parasite while lipoylation of apicoplast proteins was not affected. Parasite growth as well as the ability of the parasites to successfully complete liver stage development by merosome formation were severely impaired but not completely blocked by 8-BOA. Liver stage parasites were most sensitive to 8-BOA treatment during schizogony, the phase of development when the parasite grows and undergoes extensive nuclear division to form a multinucleated syncytium. Live cell imaging as well as immunofluorescence analysis and electronmicroscopy studies revealed a close association of both host cell and parasite mitochondria with the parasitophorous vacuole membrane suggesting that host cell mitochondria might be involved in lipoic acid uptake by the parasite from the host cell.
authors: Bernhard Nocht Institute for Tropical Medicine, Department of Molecular Parasitology, Malaria Laboratory I, Hamburg, Germany. descherm@bnihamburg.de
authors: Christina
authors: C
authors: Deschermeier
authors: Leonie-Sophie
authors: LS
authors: Hecht
authors: Frauke
authors: F
authors: Bach
authors: Katharina
authors: K
authors: Rützel
authors: Rebecca R
authors: RR
authors: Stanway
authors: Andreas
authors: A
authors: Nagel
authors: Frank
authors: F
authors: Seeber
authors: Volker T
authors: VT
authors: Heussler
mesh_terms: D002210:Caprylates / Q000494:pharmacology; D054889:Fatty Acid Synthase, Type II / Q000378:metabolism; D056945:Hep G2 Cells; D006790:Host-Parasite Interactions; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D050356:Lipid Metabolism; D054878:Lipoylation; D008099:Liver / Q000469:parasitology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development*; D021381:Protein Transport; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D008063:Thioctic Acid / Q000378:metabolism*; D014158:Transcription, Genetic; D014617:Vacuoles / Q000378:metabolism
chemical_list: D002210:Caprylates; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D008063:Thioctic Acid; D054889:Fatty Acid Synthase, Type II