Adaptation of Plasmodium falciparum to growth in medium lacking a lipids supplement is associated with mutations in the pfndh2 gene

The complex life cycle of the malaria parasite Plasmodium falciparum involves many different environments. Additionally, the parasite encounters fluctuating conditions within the same niche. For example, in the human blood parasites face variability in the host's immune response, presence of antimalarial drugs or availability of nutrients, among others. Bet-hedging adaptive strategies, which involve population heterogeneity that precedes changes in the environment, play an important role in the adaptation of P. falciparum asexual blood stages to fluctuations in their environment. This is linked to clonally variant expression, regulated at the epigenetic level, of a large number of malarial genes. However, currently there are very few examples of fluctuating conditions to which adaptation by changes in the expression of clonally variant genes has been established. Here we studied the adaptation of P. falciparum cultures to grow in the absence of an external source of lipids. In three independent adaptation experiments, cultures were able to grow without lipids in the culture medium and this was linked to acquisition of deletions or non-sense mutations in the pfndh2 gene, a component of the mitochondrial electron transport chain. In contrast, full transcriptome analysis did not provide evidence for a role for bet-hedging adaptive strategies in the adaptation of parasites to grow in lipid-free medium. Therefore, adaptation to this type of stress involved metabolic rewiring achieved by inactivation of a gene involved in the mitochondrial respiratory chains.