Selective Disruption of Mitochondrial Thiol Redox State in Cells and In Vivo.

TitleSelective Disruption of Mitochondrial Thiol Redox State in Cells and In Vivo.
Publication TypeJournal Article
Year of Publication2019
AuthorsBooty, LM, Gawel, JM, Cvetko, F, Caldwell, ST, Hall, AR, Mulvey, JF, James, AM, Hinchy, EC, Prime, TA, Arndt, S, Benincá, C, Bright, TP, Clatworthy, MR, Ferdinand, JR, Prag, HA, Logan, A, Prudent, J, Krieg, T, Hartley, RC, Murphy, MP
JournalCell Chem Biol
Volume26
Issue3
Pagination449-461.e8
Date Published2019 Mar 21
ISSN2451-9448
Abstract

Mitochondrial glutathione (GSH) and thioredoxin (Trx) systems function independently of the rest of the cell. While maintenance of mitochondrial thiol redox state is thought vital for cell survival, this was not testable due to the difficulty of manipulating the organelle's thiol systems independently of those in other cell compartments. To overcome this constraint we modified the glutathione S-transferase substrate and Trx reductase (TrxR) inhibitor, 1-chloro-2,4-dinitrobenzene (CDNB) by conjugation to the mitochondria-targeting triphenylphosphonium cation. The result, MitoCDNB, is taken up by mitochondria where it selectively depletes the mitochondrial GSH pool, catalyzed by glutathione S-transferases, and directly inhibits mitochondrial TrxR2 and peroxiredoxin 3, a peroxidase. Importantly, MitoCDNB inactivates mitochondrial thiol redox homeostasis in isolated cells and in vivo, without affecting that of the cytosol. Consequently, MitoCDNB enables assessment of the biomedical importance of mitochondrial thiol homeostasis in reactive oxygen species production, organelle dynamics, redox signaling, and cell death in cells and in vivo.

DOI10.1016/j.chembiol.2018.12.002
Alternate JournalCell Chem Biol
Citation Key10.1016/j.chembiol.2018.12.002
PubMed ID30713096