Fig. 6: Proposed model for the role of K13 in ART resistance.

K13 mutations are associated with an up-regulation of protein folding as well as proteasome-linked protein turnover that may provide a growth advantage via a greater capacity of the mutant parasite to target and eliminate damaged proteins caused by the proteotoxic ART drug. K13 also appears to be involved in other novel pathways including intracellular signaling, pyruvate metabolism, purine salvage, and the mitochondrial electron transport chain (ETC). These functions suggest an altered central carbon metabolism and represent a quiescent state maintained by the parasite that allows for a recovery advantage following DHA exposure. DHA inhibits hemoglobin uptake or degradation and induces stalling in both K13 mutant (MUT) and wild-type (WT) rings. Recovery in K13 mutants may occur through enhanced mitochondrial ATP metabolic function and remodeling of the parasite’s secretory and vesicular transport processes. Inhibition of mitochondrial ETC activity lowers the survival of K13 mutant parasites to DHA treatment.