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In the Light of Evolution Volume IV: The Human Condition
To a limited extent, the reducing equivalents of mitochondrial NADH + H+ and NADPH + H+ can also be transferred to the cytosol. Reducing equivalents from NADH + H+ can be exported via the mitochondrial inner membrane aspartate–malate shuttle. Mitochondrial NADPH + H+ can be exported to the cytosol via citrate, which is converted to malate. Malate is then oxidized by the cytosolic malic enzyme to pyruvate in association with the reduction of NADP+ to NADPH + H+. Cytosolic NADPH + H+ can also be generated by glucose 6-phosphate dehydrogenase (Wallace et al., 2010).
The cytosolic NADPH + H+ redox state is approximately –393 V. This can drive cytosolic glutathione reductase and associated glutathione peroxidases to buffer cytosolic ROS and the glutaredoxins to regulate the redox status of proteins. Cytosolic NADPH + H+ also determines the redox status of the cytosolic and nuclear thioredoxin-1(SH)2/SS [Trx1(SH)2/SS]. Trx1(SH)2/SS donates reducing equivalents to cytosolic peroxidoxins to control radicals, and to the thiol/disulfides of enzymes and transcription factors to regulate their activity. Trx1(SH)2/SS directly regulates proteins such as Oct-4, but also regulates the redox status of the bifunctional apurinic/apyrimidinic endonuclease/redox factor-1(APE/Ref1Red/Ox). The redox state of APE/Ref1Red/Ox, in turn, modulates the activity of a variety of transcription factors including activator protein-1 (AP1, c-Jun), NF-E2–related factor–2 (Nrf2), NF-κB, p53, glucocorticoid receptor (GR), estrogen receptor (ER), and hypoxia-inducible factor-1α (HIF-1α) (Kemp et al., 2008; Wallace et al., 2010).
Mitochondrially modulated ROS production also regulates the activity of a wide spectrum of enzymes, including tyrosine and serine/threonine kinases, multiple phosphatases, and NF-κB–mediated cytokine and inflammatory responses (Wallace et al., 2010). ROS levels as well as oxygen tension directly regulate the activation of the HIF-1α transcription factor. HIF-1α is constitutively synthesized but is inactivated in the presence of high O2 by hydroxylation via prolyl hydroxylase domain protein 2 (PHD2). Reduced O2 and mitochondrially generated ROS production can inhibit PHD2 activity, stabilizing HIF-1α. HIF-1α together with HIF-1 then act as a transcription factor to induce the expression of glycolytic enzymes and vascularization and hematopoietic factors, alter the oxygen affinity of OXPHOS complex IV by inducing subunit COX4-2 and the mitochondrial LON protease to degrade subunit COX4-1, induce pyruvate dehydrogenase (PDH) kinase 1 to inhibit PDH, and thus block the conversion of pyruvate to acetyl-CoA, induce MXI-1 to inhibit Myc, thus reducing expression of PGC-1α, and induce BNIP3 to initiate the autophagic degradation of the mitochondria (Semenza, 2008; Wallace et al., 2010). Hence, energy flux through the animal cell regulates virtually every aspect of cellular growth, differentiation, quiescence, and death.