Abstract
Tryparedoxin peroxidases, distant relatives of glutathione peroxidase 4 in higher eukaryotes, are responsible for the detoxification of lipid-derived hydroperoxides in African trypanosomes. The lethal phenotype of procyclic Trypanosoma brucei that lack the enzymes fulfils all criteria defining a form of regulated cell death termed ferroptosis. Viability of the parasites is preserved by α-tocopherol, ferrostatin-1, liproxstatin-1 and deferoxamine. Without protecting agent, the cells display, primarily mitochondrial, lipid peroxidation, loss of the mitochondrial membrane potential and ATP depletion. Sensors for mitochondrial oxidants and chelatable iron as well as overexpression of a mitochondrial iron-superoxide dismutase attenuate the cell death. Electron microscopy revealed mitochondrial matrix condensation and enlarged cristae. The peroxidase-deficient parasites are subject to lethal iron-induced lipid peroxidation that probably originates at the inner mitochondrial membrane. Taken together, ferroptosis is an ancient cell death program that can occur at individual subcellular membranes and is counterbalanced by evolutionary distant thiol peroxidases.
Highlights
Ferroptosis is characterized by the iron-dependent accumulation of cellular lipid hydroperoxides to lethal levels
The results suggest that ferroptosis is an ancient cell death program which exists in T. brucei; and that, in the insect stage of the parasite’s life cycle, this process first damages the mitochondrion
In PC T. brucei, deletion of the px I-III locus is lethal but the mutant cells proliferate like wildtype parasites if the medium is supplemented with either 100 mM of Trolox or Dfx (Schaffroth et al, 2016)
Summary
Ferroptosis is characterized by the iron-dependent accumulation of cellular lipid hydroperoxides to lethal levels. Unless enzymes known as peroxidases come to repair the oxidized lipids, the cell dies in a process called ferroptosis Scientists know that this death mechanism is programmed into the cells of humans and other complex eukaryotes. Bogacz and Krauth-Siegel wanted to know if ferroptosis exists in creatures that appeared early in the evolution of eukaryotes, such as the trypanosome Trypanosoma brucei This single-cell parasite causes sleeping sickness in humans and a disease called nagana in horses and cattle. Problems in the membranes of the mitochondrion stop the compartment from working properly These peroxidases-free trypanosomes fare better if they are exposed to molecules that prevent iron from taking part in the reactions that can harm lipids. Our data show that oxidants and iron in the mitochondrial matrix play a critical role in the process and that ferroptosis is an evolutionary ancient cell death program that is prevented by distant thiol peroxidases
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