Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury

This study examined the role of Akt in improving mitochondrial function in DCVC- injured RPTC. Our data show a novel observation that phosphorylated (active) Akt is localized in mitochondria of noninjured RPTC, both in mitoplasts and the mitochondrial outer membrane. Mitochondrial levels of active Akt decreased in nephrotoxicant-injured RPTC, and this decrease was associated with mitochondrial dysfunction. DCVC decreased basal, uncoupled, and state 3 respirations; ATP production; activities of complexes I, II, and III; the mitochondrial membrane potential (Delta psi m); and F0F1-ATPase activity. Expressing constitutively active Akt in DCVC- injured RPTC increased the levels of phosphorylated Akt in mitochondria, reduced the decreases in basal and uncoupled respirations, increased complex I-coupled state 3 respiration and ATP production, enhanced activities of complex I, complex III, and F0F1-ATPase, and improved Delta psi m. In contrast, inhibiting Akt activation by expressing dominant negative (inactive) Akt or using 20 mu M LY294002 exacerbated decreases in electron transport rate, state 3 respiration, ATP production, Delta psi m, and activities of complex I, complex III, and F0F1-ATPase. In conclusion, our data show that Akt activation promotes mitochondrial respiration and ATP production in toxicant-injured RPTC by 1) improving integrity of the respiratory chain and maintaining activities of complex I and complex III, 2) reducing decreases in Delta psi m, and 3) restoring F0F1-ATPase activity.