Plasmodium falciparum mitochondrial electron transport chain (Pf mETC) (Pf mETC)

The Plasmodium falciparum mitochondrial electron transport chain (mETC) is a critical metabolic pathway and a validated target for antimalarial therapy (Biagini et al., 2006). In the asexual blood stages of the parasite, the mETC's primary role is not ATP synthesis—which is largely driven by glycolysis—but rather the regeneration of ubiquinone (Painter et al., 2007). Ubiquinone acts as an essential electron acceptor for dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway required for DNA and RNA production (Vaidya & Mather, 2009). Inhibition of the mETC, particularly at the cytochrome bc1 complex (Complex III), leads to a collapse of the mitochondrial membrane potential and the cessation of pyrimidine synthesis, ultimately resulting in parasite death (Fisher et al., 2020). Drugs such as atovaquone target the Qo site of the cytochrome bc1 complex, while newer candidates like DSM265 target DHODH directly (Phillips et al., 2015). However, the rapid emergence of resistance due to point mutations in the mitochondrial-encoded cytochrome b gene remains a significant therapeutic challenge (Goodman et al., 2017).

Other names

Plasmodium falciparum mitochondrial respiratory chainPlasmodium falciparum mitochondrial membrane potentialPf mETCPlasmodium falciparum mitochondrial electron transport chain

Inhibition of the cytochrome bc1 complex or dihydroorotate dehydrogenase to disrupt electron flow and pyrimidine biosynthesis (Painter et al., 2007; Phillips et al., 2015).