Tryparedoxin peroxidase-deficiency commits trypanosomes to ferroptosis-type cell death

• Published in: eLife Vol. 7
• Main Authors: Bogacz, Marta, Krauth-Siegel, R Luise
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 26.07.2018; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adenosine Triphosphate - metabolism; Animals; Apoptosis; Beef cattle; Biochemistry; Cell Biology; Cell death; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Cells (Biology); Cristae; Cytoprotection; Deferoxamine; Detoxification; Displays (Marketing); Electron microscopy; Enzymes; Ferroptosis; Flow cytometry; Fungi; Glutathione peroxidase; Iron; Iron - metabolism; Lipid Peroxidation; Lipids; Membrane lipids; Membrane potential; Microscopy; Mitochondria; Mitochondria - metabolism; Mitochondrial Membranes - metabolism; Oxidants; Oxidants - metabolism; Oxidation-reduction reactions; Parasites; Parasites - metabolism; Peroxidase; Peroxidases - metabolism; Phenotype; Phenotypes; Protozoan Proteins - metabolism; Scientists; Sensors; Software; Superoxide dismutase; Superoxide Dismutase - metabolism; Superoxides; Thiols; Tocopherols; Trypanosoma brucei; Trypanosoma brucei brucei - enzymology; Trypanosoma brucei brucei - ultrastructure; Trypanosomiasis; trypanothione; Tryparedoxin peroxidase; Vitamin E; tryparedoxin peroxidase; trypanothione; cell biology; ferroptosis; Trypanosoma brucei
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.37503

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. Plants, animals and fungi all belong to a group of organisms known as eukaryotes. Their cells host a variety of compartments, with each having a specific role. For example, mitochondria are tasked with providing the energy that powers most of the processes that keep the cell alive. Membranes delimit these compartments, as well as the cells themselves. Iron is an element needed for chemical reactions that are essential for the cell to survive. Yet, the byproducts of these reactions can damage – ‘oxidize’ – the lipid molecules that form the cell’s membranes, including the one around mitochondria. 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. However, Bogacz and Krauth-Siegel wanted to know if ferroptosis also 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. Before it infects a mammal, T. brucei goes through an ‘insect stage’ where it lives in the tsetse fly; there, it relies on its mitochondrion to produce energy. Bogacz and Krauth-Siegel now show that if the parasites in the insect stage do not have a specific type of peroxidases, they die within a few hours. In particular, 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. They also survive more if they are forced to create large amounts of an enzyme that relies on iron to protect the mitochondrion against oxidation. Finally, using drugs that prevent ferroptosis in human cells completely rescues these trypanosomes. Taken together, 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. This last finding could be particularly relevant because the role of mitochondria in ferroptosis in mammals is highly debated. Yet, most of the research is done in cells that do not rely on this cellular compartment to get their energy. During their life cycle, trypanosomes are either dependent on their mitochondria, or they can find their energy through other sources: this could make them a good organism in which to dissect the precise mechanisms of ferroptosis.