A tryparedoxin-coupled biosensor reveals a mitochondrial trypanothione metabolism in trypanosomes

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Abstract

Trypanosomes have a trypanothione redox metabolism that provides the reducing equivalents for numerous essential processes, most being mediated by tryparedoxin (Tpx). While the biosynthesis and reduction of trypanothione are cytosolic, the molecular basis of the thiol redox homeostasis in the single mitochondrion of these parasites has remained largely unknown. Here we expressed Tpx-roGFP2, roGFP2-hGrx1 or roGFP2 in either the cytosol or mitochondrion of Trypanosoma brucei. We show that the novel Tpx-roGFP2 is a superior probe for the trypanothione redox couple and that the mitochondrial matrix harbors a trypanothione system. Inhibition of trypanothione biosynthesis by the anti-trypanosomal drug Eflornithine impairs the ability of the cytosol and mitochondrion to cope with exogenous oxidative stresses, indicating a direct link between both thiol systems. Tpx depletion abolishes the cytosolic, but only partially affects the mitochondrial sensor response to H₂O₂. This strongly suggests that the mitochondrion harbors some Tpx and, another, as yet unidentified, oxidoreductase.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Samantha Ebersoll

Biochemie-Zentrum (BZH), Universität Heidelberg, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
Marta Bogacz

Biochemie-Zentrum (BZH), Universität Heidelberg, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
Lina M Günter

Biochemie-Zentrum (BZH), Universität Heidelberg, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
Tobias P Dick

Biochemie-Zentrum (BZH), Universität Heidelberg, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
R Luise Krauth-Siegel

Biochemie-Zentrum (BZH), Universität Heidelberg, Heidelberg, Germany

For correspondence
luise.krauth-siegel@bzh.uni-heidelberg.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2164-8116

Funding

Deutsche Forschungsgemeinschaft (Kr1242/8-1)

R Luise Krauth-Siegel

Deutsche Forschungsgemeinschaft (SPP 1710 Kr1242/6-2)

R Luise Krauth-Siegel

Deutsche Forschungsgemeinschaft (SPP 1710 Di731/3-2)

Tobias P Dick

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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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.