| The concept of the mitochondrial energy-redox axis integrates the mitochondrial energy-transduction and redox status as a concerted process with the two components inter-linked by the reducing equivalents (i.e., NAD(P) +/NAD(P)H). Decrease of mitochondrial energy transduction and pro-oxidant shift of cellular redox status precede the pathological changes of several diseases (i.e., diabetes) and are key features of aging. Mitochondria are also recipients of cellular signaling regulations such as MAPKs and PI3K/AKT pathway of insulin signaling. These studies are aimed at assessing the effect of the PI3K/AKT signaling pathway in the mitochondrial energy-redox axis and depicting the molecular mechanisms inherent in the effect. A liver-specific Pten deletion model that shows a robust insulin signaling was used to study how the PI3K/AKT pathways affect the mitochondrial energy-redox axis. The hypothesis to be tested is that liver-specific Pten deletion up-regulates mitochondrial bioenergetics through modulation of PI3K/AKT signaling pathways, which further affect mitochondrial and cellular H2O2 homeostasis, redox status, and the intrinsic apoptotic pathway.;These studies revealed that mitochondrial bioenergetics is regulated by PI3K/AKT signaling through three mechanisms: 1) AKT increases glycolysis and thus, a higher substrate (pyruvate) supply to mitochondria; 2) AKT, upon activation, translocates to mitochondria and phosphorylates ATP synthase subunits &agr;/beta leading to a higher ATP synthase activity; 3) AKT phosphorylates / inactivates GSK3beta, which is correlated with the decrease of the phosphorylation (inactivation) of mitochondria PDH-E1&agr; at Ser273. These effects translate in a higher bioenergetic capacity of mitochondria and, consequently, a lower generation of H2O2 by these organelles. This is attributed to: 1) the highly oxidized state of the mitochondrial respiratory complexes; 2) the higher expression of mitochondrial and cellular H 2O2 removal enzymes; 3) through modulation of the expression of mitochondrial isocitrate dehydrogenase-2 and consequently the increased generation of reducing equivalents (NADPH), which are critical for the mitochondrial H2O2 removal system. The study of AKT activation on mitochondria as a function of age shows that mitochondria of Pten -/- liver have a significantly reduced H2O 2 generation level than control at older age (9--12 month old) and AKT activation antagonizes the increase of mitochondrial source of H2O2 production caused by aging. |
