Plasmodium mitochondrial respiratory chain (mETC)

The Plasmodium mitochondrial respiratory chain (mETC) is a critical metabolic pathway located in the inner mitochondrial membrane of malaria parasites, distinct from its human counterpart in both structure and primary function [1, 3]. In the disease-causing asexual blood stages of Plasmodium falciparum, the mETC acts essentially as an electron sink for the enzyme dihydroorotate dehydrogenase (DHODH), which is vital for de novo pyrimidine biosynthesis [7, 14]. Since the parasite cannot salvage pyrimidines from the host, inhibition of the mETC effectively halts DNA and RNA synthesis, leading to parasite death or growth arrest [8, 9]. The chain consists of several dehydrogenases and proton-pumping complexes, with the cytochrome bc1 complex (Complex III) being a major validated drug target for the antimalarial drug atovaquone [2, 10]. Although highly effective, the utility of drugs targeting this pathway is frequently compromised by the rapid development of resistance mutations in the parasite's mitochondrial genome [11, 12]. Consequently, modern drug development focuses on combination therapies and novel inhibitors of diverse mETC components to circumvent existing resistance mechanisms [2, 13].

Other names

Electron transport chainMitochondrial electron transport chainmtETCRespiratory chainMitochondrial electron transport system

Inhibition of electron transport, primarily by targeting the cytochrome bc1 complex (Complex III) or dihydroorotate dehydrogenase (DHODH), which disrupts de novo pyrimidine biosynthesis and leads to the collapse of the mitochondrial membrane potential [1, 8, 14].