NAD(P) transhydrogenase has vital non‐mitochondrial functions in malaria parasite transmission

• Published in: EMBO reports Vol. 21; no. 3; pp. e47832 - n/a
• Main Authors: Saeed, Sadia, Tremp, Annie Z, Sharma, Vikram, Lasonder, Edwin, Dessens, Johannes T
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 04.03.2020; John Wiley and Sons Inc
• Subjects: Adenine; Animals; Biosynthesis; Cofactors; Cytoplasmic membranes; Disease transmission; Enzymatic activity; Infectivity; Isoforms; Malaria; Malaria - transmission; Membranes; Mitochondria; Mitochondria - genetics; NAD; NADP; NADP Transhydrogenases - genetics; NADPH; Nicotinamide; Nicotinamide adenine dinucleotide; oocyst; ookinete; Organelles; Parasites; Plasmodium; Sporogony; sporozoite; Sporozoites; transhydrogenase; transmission; Vector-borne diseases; Vertebrates; Zygotes; transhydrogenase; ookinete; sporozoite; oocyst; transmission; malaria
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201947832

Nicotinamide adenine dinucleotide (NAD) and its phosphorylated form (NADP) are vital for cell function in all organisms and form cofactors to a host of enzymes in catabolic and anabolic processes. NAD(P) transhydrogenases (NTHs) catalyse hydride ion transfer between NAD(H) and NADP(H). Membrane‐bound NTH isoforms reside in the cytoplasmic membrane of bacteria, and the inner membrane of mitochondria in metazoans, where they generate NADPH. Here, we show that malaria parasites encode a single membrane‐bound NTH that localises to the crystalloid, an organelle required for sporozoite transmission from mosquitos to vertebrates. We demonstrate that NTH has an essential structural role in crystalloid biogenesis, whilst its enzymatic activity is required for sporozoite development. This pinpoints an essential function in sporogony to the activity of a single crystalloid protein. Its additional presence in the apicoplast of sporozoites identifies NTH as a likely supplier of NADPH for this organelle during liver infection. Our findings reveal that Plasmodium species have co‐opted NTH to a variety of non‐mitochondrial organelles to provide a critical source of NADPH reducing power. Synopsis Membrane‐bound NTH is a mitochondrial NADPH‐generating enzyme. In malaria parasites it is found in distinct organelles, the crystalloid in ookinetes and the apicoplast in sporozoites, and has specific roles in sporozoite formation and infectivity. Plasmodium NAD(P) transhydrogenase (NTH) has an unusual βα domain architecture. NTH has an essential structural role in crystalloid biogenesis in malaria parasites. Crystalloid‐resident NTH has an essential enzymatic role in sporozoite formation. Apicoplast‐resident NTH activity contributes to the transition from sporozoite to intraerythrocytic parasites. Membrane‐bound NTH is a mitochondrial NADPH‐generating enzyme. In malaria parasites it is found in distinct organelles, the crystalloid in ookinetes and the apicoplast in sporozoites, and has specific roles in sporozoite formation and infectivity.