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Antioxid Redox Signal. 2012 Dec 15;17(12):1714-27. doi: 10.1089/ars.2012.4639. Epub 2012 Jun 11.

Mitochondrial thiols in the regulation of cell death pathways.

Author information

1
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

SIGNIFICANCE:

Regulation of mitochondrial H(2)O(2) homeostasis and its involvement in the regulation of redox-sensitive signaling and transcriptional pathways is the consequence of the concerted activities of the mitochondrial energy- and redox systems.

RECENT ADVANCES:

The energy component of this mitochondrial energy-redox axis entails the formation of reducing equivalents and their flow through the respiratory chain with the consequent electron leak to generate [Formula: see text] and H(2)O(2). The mitochondrial redox component entails the thiol-based antioxidant system, largely accounted for by glutathione- and thioredoxin-based systems that support the activities of glutathione peroxidases, peroxiredoxins, and methionine sulfoxide reductase. The ultimate reductant for these systems is NADPH: mitochondrial sources of NADPH are the nicotinamide nucleotide transhydrogenase, isocitrate dehydrogenase-2, and malic enzyme. NADPH also supports the glutaredoxin activity that regulates the extent of S-glutathionylation of mitochondrial proteins in response to altered redox status.

CRITICAL ISSUES:

The integrated network of these mitochondrial thiols constitute a regulatory device involved in the maintenance of steady-state levels of H(2)O(2), mitochondrial and cellular redox and metabolic homeostasis, as well as the modulation of cytosolic redox-sensitive signaling; disturbances of this regulatory device affects transcription, growth, and ultimately influences cell survival/death.

FUTURE DIRECTIONS:

The modulation of key mitochondrial thiol proteins, which participate in redox signaling, maintenance of the bioenergetic machinery, oxidative stress responses, and cell death programming, provides a pivotal direction in developing new therapies towards the prevention and treatment of several diseases.

PMID:
22530585
PMCID:
PMC3474184
DOI:
10.1089/ars.2012.4639
[Indexed for MEDLINE]
Free PMC Article

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