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Disruption of Redox Homeostasis by Enzymatic Activation of a Triakylphosphine Probe in Mitochondria

preprint
submitted on 28.08.2019 and posted on 30.08.2019 by Jade Nguyen, Alina Tirla, Pablo Rivera-Fuentes
Redox homeostasis is essential for cell function and its disruption is associated with cancer, metabolic and neurodegenerative diseases. Redox balance is largely regulated by the relative concentrations of reduced and oxidized glutathione. In eukaryotes, this ratio is different in each cell compartment, and disruption of the mitochondrial redox balance has been specifically linked to pathologies such as obesity and type II diabetes. Although reduced glutathione can be scavenged using electrophiles, there is a lack of probes that can produce it. In this study, we report an organellespecific reducing agent based on tributylphosphine that selectively reduces oxidized glutathione in mitochondria. This probe is activated by endogenous nitroreductases and subsequently releases tributylphosphine, as well as a fluorescent reporter, within the organelle. Confocal imaging and biological assays in human cells revealed that, counterintuitively, increased reduced glutathione induced oxidative stress through accumulation of superoxide. Transcriptomic analysis was used to establish that mitochondrial redox stress activates a cellular response orchestrated by transcription factor ATF4, which upregulates genes involved in glutathione metabolism.

Funding

Swiss National Science Foundation SNSF grant 200021_165551

History

Email Address of Submitting Author

pablo.riverafuentes@epfl.ch

Institution

EPF Lausanne

Country

Switzerland

ORCID For Submitting Author

0000-0001-8558-2828

Declaration of Conflict of Interest

The authors declare no competing interests

Version Notes

before peer review

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