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

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

doi:10.1128/mbio.01718-23

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

mBio. 2023 Oct 26;14(6):e0171823. doi: 10.1128/mbio.01718-23. Online ahead of print.

Authors

Emma Pietsch^{1

2

3}, Abhinay Ramaprasad⁴, Sabrina Bielfeld^{1

2

3}, Yvonne Wohlfarter⁵, Bohumil Maco⁶, Korbinian Niedermüller^{1

2

3}, Louisa Wilcke^{1

2

3}, Joachim Kloehn⁶, Markus A Keller⁵, Dominique Soldati-Favre⁶, Michael J Blackman^{4

7}, Tim-Wolf Gilberger^{1

2

3}, Paul-Christian Burda^{1

2

3}

Affiliations

¹ Centre for Structural Systems Biology , Hamburg, Germany.
² Bernhard Nocht Institute for Tropical Medicine , Hamburg, Germany.
³ University of Hamburg , Hamburg, Germany.
⁴ Malaria Biochemistry Laboratory, The Francis Crick Institute , London, United Kingdom.
⁵ Institute of Human Genetics, Medical University of Innsbruck , Innsbruck, Austria.
⁶ Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva , Geneva, Switzerland.
⁷ Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine , London, United Kingdom.

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. 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.

Keywords: cardiolipin; electron transport chain; malaria; mitochondrion; patatin-like phospholipase.

Abstract

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