Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

Abstract

Artemisinin and its semi-synthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstream Plasmodium parasites that enter into and later reactivate from a dormant persister state. Here we show that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Persister forms exhibit restructured mitochondrial-nuclear associations and an altered metabolic state consistent with stress from reactive oxygen species. New contacts between the mitochondria and nuclei may support communication pathways of mitochondrial retrograde signaling, resulting in transcriptional changes in the nucleus as a survival response. Further characterization of the organellar interactions and metabolic dependencies of persisters may suggest strategies to combat recrudescences of malaria after treatment.

A PCR-Based Technique to Track the Geographic Origin of Plasmodium falciparum With 23-SNP Barcode Analysis

“…Ribosomes of the Plasmodium apico and mt have been validated as targets for antibiotic action (23). It has also been reported that the artemisinin-exposed persistent forms restructured the mitochondrial-nuclear associations in P. falciparum (24). In contrast, rapid killing of malaria parasites by artemisinin is thought to result from depolarization of the mitochondrial membrane (25).…”