Journal Article

PUBDB-2024-00239

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A patatin-like phospholipase is important for mitochondrial function in malaria parasites

Pietsch, E.CSSB* ; Ramaprasad, A. ; Bielfeld, S.CSSB* ; Wohlfarter, Y. ; Maco, B. ; Niedermüller, K. ; Wilcke, L.CSSB* ; Kloehn, J. ; Keller, M. A. ; Soldati-Favre, D. ; Blackman, M. J. ; Gilberger, T.CSSB* ; Burda, P.-C. (Corresponding author)CSSB*

2023
American Society for Microbiology Washington, DC

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Please use a persistent id in citations: doi:10.1128/mbio.01718-23  doi:10.3204/PUBDB-2024-00239

Abstract: Plasmodium parasites rely on a functional electron transport chain (ETC) within their mitochondrion for proliferation, and compounds targeting mitochondrial functions are validated antimalarials. Here, we localize Plasmodium falciparum patatin-like phospholipase 2 (PfPNPLA2, PF3D7_1358000) to the mitochondrion and reveal that disruption of the PfPNPLA2 gene impairs asexual replication. PfPNPLA2-null parasites are hypersensitive to proguanil and inhibitors of the mitochondrial ETC, including atovaquone. In addition, PfPNPLA2-deficient parasites show reduced mitochondrial respiration and reduced mitochondrial membrane potential, indicating that disruption of PfPNPLA2 leads to a defect in the parasite ETC. Lipidomic analysis of the mitochondrial phospholipid cardiolipin (CL) reveals that loss of PfPNPLA2 is associated with a moderate shift toward shorter-chained and more saturated CL species, implying a contribution of PfPNPLA2 to CL remodeling. PfPNPLA2-deficient parasites display profound defects in gametocytogenesis, underlining the importance of a functional mitochondrial ETC during both the asexual and sexual development of the parasite. IMPORTANCEFor their proliferation within red blood cells, malaria parasites depend on a functional electron transport chain (ETC) within their mitochondrion, which is the target of several antimalarial drugs. Here, we have used gene disruption to identify a patatin-like phospholipase, PfPNPLA2, as important for parasite replication and mitochondrial function in Plasmodium falciparum. Parasites lacking PfPNPLA2 show defects in their ETC and become hypersensitive to mitochondrion-targeting drugs. Furthermore, PfPNPLA2-deficient parasites show differences in the composition of their cardiolipins, a unique class of phospholipids with key roles in mitochondrial functions. Finally, we demonstrate that parasites devoid of PfPNPLA2 have a defect in gametocyte maturation, underlining the importance of a functional ETC for parasite transmission to the mosquito vector.

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Contributing Institute(s):

1. CSSB-BNITM-TG (CSSB-BNITM-TG)
2. CSSB-CF-ALFM (CSSB-CF-ALFM)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)
2. DFG project G:(GEPRIS)414222880 - Funktionelle Charakterisierung der Phospholipasen im Malariaerreger Plasmodium falciparum (414222880) (414222880)
3. MalariaEgress - Role of perforin-like proteins and phospholipases in malaria parasite egress (751865) (751865)
4. DFG project 446556156 - Identifizierung und Charakterisierung neuer Faktoren, welche die Freisetzung von Plasmodium falciparum aus roten Blutzellen ermöglichen (446556156) (446556156)
5. ToxoPersist - Molecular Basis of Toxoplasma gondii Encystation and Persistence (695596) (695596)

Experiment(s):

1. No specific instrument

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