The Francis Crick Institute
pietsch-et-al-2023-a-patatin-like-phospholipase-is-important-for-mitochondrial-function-in-malaria-parasites (1).pdf (4.77 MB)

A patatin-like phospholipase is important for mitochondrial function in malaria parasites.

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journal contribution
posted on 2024-01-10, 10:58 authored by Emma Pietsch, Abhinay Ramaprasad, Sabrina Bielfeld, Yvonne Wohlfarter, Bohumil Maco, Korbinian Niedermüller, Louisa Wilcke, Joachim Kloehn, Markus A Keller, Dominique Soldati-Favre, Michael J Blackman, Tim-Wolf Gilberger, Paul-Christian Burda
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. IMPORTANCE For 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.


Crick (Grant ID: CC2129, Grant title: Blackman CC2129) European Commission (Grant ID: 751865 - MalariaEgress, Grant title: EC 751865 - MalariaEgress)