Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury
| Autor: | E. Kim Fifer, Grazyna Nowak, Zabeena P. Shaik |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Necrosis
Physiology Morpholines Oxidative phosphorylation Biology Mitochondrion Transfection Oxidative Phosphorylation Article Electron Transport Electron Transport Complex IV Kidney Tubules Proximal chemistry.chemical_compound Electron Transport Complex III Adenosine Triphosphate Oxygen Consumption medicine Animals Cysteine Enzyme Inhibitors Phosphorylation Protein kinase B Cells Cultured Membrane Potential Mitochondrial Electron Transport Complex I urogenital system Electron Transport Complex II Cell biology Mitochondria Proton-Translocating ATPases chemistry Mitochondrial permeability transition pore Chromones Mitochondrial Membranes Environmental Pollutants Kidney Diseases Oligomycins Rabbits medicine.symptom Adenosine triphosphate Proto-Oncogene Proteins c-akt Intracellular |
| Zdroj: | American journal of physiology. Renal physiology. 294(2) |
| ISSN: | 1931-857X |
| Popis: | Previously, we showed that protein kinase B (Akt) activation increases intracellular ATP levels and decreases necrosis in renal proximal tubular cells (RPTC) injured by the nephrotoxicant S-(1, 2-dichlorovinyl)-l-cysteine (DCVC) (Shaik ZP, Fifer EK, Nowak G. Am J Physiol Renal Physiol 292: F292–F303, 2007). 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 (ΔΨm); 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 ΔΨm. In contrast, inhibiting Akt activation by expressing dominant negative (inactive) Akt or using 20 μM LY294002 exacerbated decreases in electron transport rate, state 3 respiration, ATP production, ΔΨm, 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 ΔΨm, and 3) restoring F0F1-ATPase activity. |
| Databáze: | OpenAIRE |
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