Microaerophilic Respiratory Metabolism of Plasmodium falciparum Mitochondrion as a Drug Target

Abstract

The Plasmodium falciparum mitochondrion is an organelle that presents structural and physiological characteristics different from mitochondria in other eukaryotes. Moreover, there are substantial differences in the properties of asexual and sexual mitochondria. One of the reasons is the adaptation of the parasite to different environments, in particular the great differences in oxygen tension between the host and the mosquito. In this review, we present a synthesis of the recent data on the ultrastructure, the genome and the physiology of the mitochondrion. We try to clarify the mitochondrial role in the intraerythrocytic environment and particularly focus on mitochondrial metabolic pathways that relate to oxidative phosphorylation, including the tricarboxylic acid cycle, de novo pyrimidine biosynthesis via dihydroorotate dehydrogenase and the particularities of the electron transport chain. In addition, we provide details on certain characteristics like the lack of pyruvate dehydrogenase, the existence of a rotenone-insensitive NADH-dehydrogenase, the possible existence of an alternative oxidase, and uncoupled proteins. Such unique particularities of parasite mitochondria could be promising targets for development of a new therapy. The elucidation of the role of this organelle in microaerophilic respiratory metabolism and the association of antimalarial drugs with hyperbaric oxygen therapy might provide new treatments for infection by P. falciparum.

Melatonin activates FIS1, DYN1, and DYN2 Plasmodium falciparum related‐genes for mitochondria fission: Mitoemerald‐GFP as a tool to visualize mitochondria structure

“…As Plasmodium mitochondria mediate various events related to drug action mechanisms and resistance, the search for proteins involved in mitochondria functions that could be potential target of pharmacological intervention in malaria. That lead us to investigate the existence of plasmodial proteins analogous to those expressed in other eukaryotes and to investigate the changes in their transcripts at the different differentiation stages of the parasites.…”

A Novel Methodology for Bioenergetic Analysis of Plasmodium falciparum Reveals a Glucose-Regulated Metabolic Shift and Enables Mode of Action Analyses of Mitochondrial Inhibitors

“…In Plasmodium spp., incorporation of pyruvate-derived acetyl-CoA into the TCA cycle or the source of acetyl-CoA has been disputed. 3,12,17,43 In aerobic cells, pyruvate dehydrogenase (PDH) converts glycolytic pyruvate to acetyl-CoA. However, this scenario has been considered unlikely for malaria parasites, which express PDH in the apicoplast but not in the mitochondrion.…”

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

“…P. falciparum mitochondrion presents structural and physiological characteristics different from mitochondria in other eukaryotes [54]. One of the reasons is the adaptation of the parasite to different environments, in particular, the great differences in oxygen tension between the host and the mosquito.…”