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processes are regulated by the availability of high-energy intermediates (Wallace and Fan, 2010; Wallace et al., 2010).

Changes in cellular redox state are also important in regulating transcription factors and metabolic pathways. The redox state of the cell reflects the flux of reducing equivalents from the mitochondrion, through the nucleus-cytosol, and on to the other cellular compartments. Reducing equivalents enter the mitochondrion as NADH + H+ at −250 mV and flow through the ETC and other cellular pathways down to oxygen at +800 mV. The importance of the subcellular redox status is illustrated by the class III histone deacetylase Sirt1. Sirt1 removes acetyl groups from proteins in the presence of NAD+ via the reaction: acetyl-lysine + NAD+ → lysine + nicotinamide + 2′-O-acetyl-ADP ribose. Although the oxidized NAD+ is a required coreactant, the reduced form of NAD+, NADH + H+, cannot be used by Sirt1. Therefore, deacetylation is coupled to the cellular redox state. The FOXO and PGC-1 transcription factors are inactivated by acetyl-CoA-mediated acetylation. They can be reactivated by deacetylation by Sirt1 + NAD+. When glucose is abundant, glycolysis reduces cytosolic NAD+ to NADH + H+ in the process of generating pyruvate. The pyruvate is converted to acetyl-CoA in the mitochondrion, and the acetyl-CoA is exported back into the cytosol, and is used to acetylate and inactivate PGC-1α and FOXO. Because the cytosolic NAD+ is reduced to NADH + H+, Sirt1 cannot deacetylate FOXO and PGC-1α, and OXPHOS is inhibited whereas glycolysis is favored. By contrast, when fatty acids and ketone bodies (acetoacetate and β-hydroxybutyrate) are metabolized, they are burned entirely within the mitochondrion, and the cytosolic NAD+ remains oxidized. The combination of Sirt1 + NAD+ then deacetylates and activates the FOXO and PGC-1α transcription factors, up-regulating OXPHOS to oxidize fats and ketones (Wallace, 2009).

The redox regulation of cellular metabolism goes far beyond its effects in Sirt1 activity. In the mitochondrion, a substantial portion of the NADH is oxidized via the ETC using O2 to generate ∆P, but the redox state of a portion of the NADH + H+ is increased by the nicotinamide nucleoside transhydrogenase (Nnt), using energy from ∆P to drive the transfer of reducing equivalents from NADH + H+ to NADPH + H+ with a redox potential of −405 mV. Mitochondrial NADPH + H+ can then drive the reduction of oxidized glutathione (GS-SG) to reduced glutathione (2GSH), and GSH can act through the glutathione peroxidases to detoxify mitochondrial ROS and other radicals. NADPH + H+ also provides reducing equivalents for mitochondrial thioredoxin-2(SH)2/SS [Trx2(SH)2/SS], to drive peroxidoxins to reduce radical species and to mediate the modulation of the redox status of thiol-disulfides of an array of mitochondrial enzymes directly regulating their activity (Kemp et al., 2008; Wallace et al., 2010).



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