Mitochondrial Thiols in the Regulation of Cell Death Pathways

Abstract

Significance: Regulation of mitochondrial H 2 O 2 homeostasis and its involvement in the regulation of redoxsensitive 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 energyredox axis entails the formation of reducing equivalents and their flow through the respiratory chain with the consequent electron leak to generate O Á À 2 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.

Mitochondrial Energy Metabolism and Redox Signaling in Brain Aging and Neurodegeneration

“…The role of mitochondrial thiols in redox signaling (165) and cell death pathways (252) has been recently reviewed. The redox potential-which is calculated of the mitochondrial GSH/glutathione disulfide (GSSG) or Trx2 red / Trx2 ox couples-is *-300 and -340 mV (116,124), respectively.…”

“…The levels of TrxR2 decrease with age in different tissues and is accompanied by enhanced susceptibility to apoptosis (201), also suggesting that NADPH supply and TrxR activity rather than activities of Trx2 may be rate limiting for the protection against oxidants and be of importance in dysregulated redox status during aging and neurodegeneration (182). The significance of the redox couples and redox catalysts for brain aging and age-related neurodegeneration just mentioned is underscored by the highly oxidized mitochondrial and cellular redox environment that is involved in these processes (146,168,252).…”

Metabolism of Preimplantation Embryo Development

“…Thus, PPP allows glucose to be metabolized to generate NADPH, R5P/X5P, and ATP. Because other energy sources, such as lipids, monocarboxylates, and amino acids, cannot directly be metabolized to G6P (a substrate for PPP), glucose becomes a crucial energy substrate in cells that require energy, b Mitochondria also have nicotinamide nucleotide transhydrogenase for NADPH production (Yin, Sancheti, & Cadenas, 2012).…”

Nitric oxide interacts with mitochondrial complex III producing antimycin-like effects

“…mg protein) (12,13) (14,15), this latter species involved in the regulation of redox sensitive signalling (18,19,20).…”