Tryparedoxin peroxidase-deficiency commits trypanosomes to ferroptosis-type cell death
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Funding
Deutsche Forschungsgemeinschaft (Kr1241/5-1)
- R Luise Krauth-Siegel
Deutsche Forschungsgemeinschaft (Kr1241/8-1)
- R Luise Krauth-Siegel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Marcus Conrad, Helmholtz Zentrum München
Publication history
- Received: April 12, 2018
- Accepted: July 24, 2018
- Accepted Manuscript published: July 26, 2018 (version 1)
- Version of Record published: August 30, 2018 (version 2)
Copyright
© 2018, Bogacz & Krauth-Siegel
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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