Glucose is toxic to glycosome-deficient trypanosomes

Abstract

Trypanosomatids, the etiologic agents of sleeping sickness, leishmaniasis, and Chagas' disease, compartmentalize glycolysis within glycosomes, metabolic organelles related to peroxisomes. Here, we identify a trypanosome homologue of PEX14, one of the components of the peroxisomal protein import docking complex. We have used double-stranded RNA interference to target the PEX14 transcript for degradation. Glycosomal matrix protein import was compromised, and both glycolytic bloodstream stage parasites and mitochondrially respiring procyclic stage parasites were killed. Thus, unlike peroxisomes, glycosomes are essential organelles. Surprisingly, procyclic forms, which can grow in the absence of glucose, were killed by PEX14 RNA interference only when simple sugars were present. Thus, interference with glycosome protein import makes glucose toxic to trypanosomes.

Glycerol 3-Phosphate Alters Trypanosoma brucei Hexokinase Activity in Response to Environmental Change

“…toxic (6). Glucose toxicity has been proposed to result from the lack of appropriate compartmentalization of TbHKs and T. brucei phosphofructokinase, leading to uncontrolled consumption of ATP (6).…”

“…It has been suggested by modeling experiments that compartmentalization prevents the unproductive consumption of the net ATP (referred to as "turbo-explosion") by either the TbHKs or T. brucei phosphofructokinase (5). RNAi studies of genes essential to glycosome biosynthesis support this observation, as glucose is toxic to PF T. brucei lacking glycosomes, presumably as a result of inappropriate consumption of cytosolic ATP (6), whereas RNAi of TbHK in the glycosome-deficient cells is protective (7).…”

Autophagy and Related processes in Trypanosomatids: Insights from Genomic and Bioinformatic Analyses

“…Significant differences are also predicted for the ATG1-containing complexes that assemble on the preautophagosomal structure, the differences between which are thought to reflect the choice of Cvt or autophagy. 13 In addition to ATG13 and ATG17 already mentioned, ATG11 (associated principally with step 2) and ATG20 appear absent in trypanosomatids. In contrast, ATG24 and VAC8 are proteins that interact with components of the ATG1-containing complex(es) that are present in trypanosomatids.…”

“…The specific roles of these proteins at step 3, and potentially at other steps, are not clear. 13 Within step 4, two conjugation systems involving ubiquitin-like proteins have been described as acting in vesicle expansion and completion in yeasts. 43 Intriguingly, one entire system is absent in trypanosomatids while the second is present.…”

Endosomes, Glycosomes, and Glycosylphosphatidylinositol Catabolism in Leishmania major

“…Consequently, peroxisomes are termed "glycosomes." Mistargeting of glycolytic enzymes to the cytosol is lethal in the bloodstream form of T. brucei (27)(28)(29), indicating that glycosomes are an essential organelle in the parasite.…”