onditional knock-out of lipoic acid protein ligase 1 reveals redundancy pathway for lipoic acid metabolism in Plasmodium berghei malaria parasite

Background:?Lipoic?acid?is a cofactor?for?a-keto?acid?dehydrogenase system that is involved?in?the central energy?metabolism.?In?the apicomplexan?parasite,?Plasmodium,?lipoic?acid?protein?ligase?1?(LplA1) and LplA2 catalyse the ligation?of?acquired?lipoic?acid?to the dehydrogenase complexes?in?the mitochondrion. The enzymes LipB and LipA mediate?lipoic?acid?synthesis and ligation to the enzymes?in?the apicoplast. These enzymes?in?the?lipoic?acid?metabolism?machinery have been shown to play important roles?in?the biology?of?Plasmodium?parasites, but the relationship between the enzymes is not fully elucidated.?Methods: We used an anhydrotetracycline (ATc)-inducible transcription system to generate transgenic P. berghei parasites in which the lplA1 gene was conditionally knocked out (LplA1-cKO). Phenotypic changes and the lplA1 and lplA2 gene expression profiles of cloned LplA1-cKO parasites were analysed.Results: LplA1-cKO parasites showed severely impaired growth in vivo in the first 8 days of infection, and retarded blood-stage development in vitro, in the absence of ATc. However, these parasites resumed viability in the late stage of infection and mounted high levels of parasitemia leading to the death of the hosts. Although lplA1 mRNA expression was regulated tightly by ATc during the whole course of infection, lplA2 mRNA expression was significantly increased in the late stage of infection only in the LplA1-cKO parasites that were not exposed to ATc. Conclusions: The lplA2 gene can be activated as an alternative pathway to compensate for the loss of LplA1 activity and to maintain lipoic acid metabolism.