Autophagy is a cell death mechanism in Toxoplasma gondii.
Nutrient sensing and the capacity to respond to starvation is tightly regulated as a means of cell survival. Among the features of the starvation response are induction of both translational repression and autophagy. Despite the fact that intracellular parasite like Toxoplasma gondii within a host cell predicted to be nutrient rich, they encode genes involved in both translational repression and autophagy. We therefore examined the consequence of starvation, a classic trigger of autophagy, on intracellular parasites. As expected, starvation results in the activation of the translational repression system as evidenced by elevation of phosphorylated TgIF2α (TgIF2α-P). Surprisingly, we also observe a rapid and selective fragmentation of the single parasite mitochondrion that leads irreversibly to parasite death. This profound effect was dependent primarily on the limitation of amino acids and involved signalling by the parasite TOR homologue. Notably, the effective blockade of mitochondrial fragmentation by the autophagy inhibitor 3-methyl adenine (3-MA) suggests an autophagic mechanism. In the absence of a documented apoptotic cascade in T. gondii, the data suggest that autophagy is the primary mechanism of programmed cell death in T. gondii and potentially other related parasites.
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Debasish
D
Ghosh
Julia L
JL
Walton
Paul D
PD
Roepe
Anthony P
AP
Sinai
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002470:Cell Survival; D002522:Chlorocebus aethiops; D003470:Culture Media / Q000378:metabolism; D004734:Energy Metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D039881:Prokaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013312:Stress, Physiological; D014122:Toxoplasma / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D014709:Vero Cells
D000596:Amino Acids; D003470:Culture Media; D039881:Prokaryotic Initiation Factor-2; C025946:3-methyladenine; D000225:Adenine; D020123:Sirolimus