Figure 9.

Schematic illustration of the mechanisms by which Akt is activated in cancer cells with mitochondrial respiration injury. Genetic factors (mtDNA mutations/deletions) and environmental factors (hypoxic conditions) cause defects in mitochondrial respiration and render the cancer cells highly dependent on glycolysis for ATP generation. This metabolic alteration leads to an increase in NADH caused by the lack of its utilization by the respiratory chain and a decrease in NADPH from the PPP. The increased NADH effectively competes with NADPH and compromises the ability of NADPH/Trx to keep PTEN protein in the reduced state, leading to inactivation of PTEN and activation of Akt. The solid arrows indicate increased activity in the respective steps; the dashed arrows indicate decreased activity.