Mitochondrial thiols in the regulation of cell death pathways

Fei Yin, Harsh Sancheti, Enrique Cadenas

Research output: Contribution to journalReview articlepeer-review

82 Scopus citations

Abstract

Significance: Regulation of mitochondrial H2O2 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 and H2O2. 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 H2O 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.

Original languageEnglish (US)
Pages (from-to)1714-1727
Number of pages14
JournalAntioxidants and Redox Signaling
Volume17
Issue number12
DOIs
StatePublished - Dec 15 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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