Understanding the biochemical significance of the mitochondrial pyruvate carrier in the rodent malarial parasite, Plasmodium berghei

Abstract

Mitochondrial pyruvate carrier (MPC) protein has been established as the key pyruvate transporter across the inner mitochondrial membrane. In Plasmodium, flux through the tricarboxylic acid (TCA) cycle is low in the asexual stages that is upregulated in the gametocytes with greater utilization of glutamine than glucose to drive the cycle. Acetyl-CoA in the mitochondrion has been established to be essential for the parasite. In this context, we established the biochemical function of P. berghei MPC as a pyruvate transporter through functional complementation in yeast. In P. berghei, both subunits, MPC1 and MPC2 were found to localize to the mitochondrion and surprisingly, were found to be non-essential for the blood stages and for ookinete formation. Through metabolite tracing studies using 13C6-glucose and 13C515N2 L-glutamine, we have derived the biochemical basis for this observed phenotype of {Delta}mpc1{Delta}mpc2 parasites. Our studies suggest the presence of an aminotransferase localized to the mitochondrion that converts alanine to pyruvate, leading to the continued production of acetyl-CoA in the organelle even in the absence of MPC. This highlights the existence of metabolic plasticity, a survival strategy, that enables the utilization of different metabolic precursors for the generation of acetyl-CoA in the mitochondrion.