This Article Full Text Full Text (PDF) All Versions of this Article: 98/10/1314    most recent 01.RES.0000222418.99976.1dv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Comellas, A. P. Articles by Sznajder, J. I. Search for Related Content PubMed PubMed Citation Articles by Comellas, A. P. Articles by Sznajder, J. I. Related Collections Cell biology/structural biology Energy metabolism Ischemic biology - basic studies

(Circulation Research. 2006;98:1314.)
© 2006 American Heart Association, Inc.

Cellular Biology

Hypoxia-Mediated Degradation of Na,K-ATPase via Mitochondrial Reactive Oxygen Species and the Ubiquitin-Conjugating System

Alejandro P. Comellas, Laura A. Dada, Emilia Lecuona, Liuska M. Pesce, Navdeep S. Chandel, Nancy Quesada, G. R. Scott Budinger, Ger J. Strous, Aaron Ciechanover, Jacob I. Sznajder

From the Division of Pulmonary and Critical Care Medicine (A.P.C., L.A.D., E.L., L.M.P., N.S.C., N.Q., G.R.S.B., A.C., J.I.S.), Feinberg School of Medicine, Northwestern University, Chicago, Ill; The Vascular and Tumor Biology Research Center (A.C.), Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; and University Medical Center Utrecht and Institute of Biomembranes (G.J.S.), Utrecht, The Netherlands.

Correspondence to Jacob I. Sznajder, MD, Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, 240 E Huron, McGaw 2-2300, Chicago, IL 60611. E-mail j-sznajder{at}northwestern.edu

We set out to determine whether cellular hypoxia, via mitochondrial reactive oxygen species, promotes Na,K-ATPase degradation via the ubiquitin-conjugating system. Cells exposed to 1.5% O₂ had a decrease in Na,K-ATPase activity and oxygen consumption. The total cell pool of 1 Na,K-ATPase protein decreased on exposure to 1.5% O₂ for 30 hours, whereas the plasma membrane Na,K-ATPase was 50% degraded after 2 hours of hypoxia, which was prevented by lysosome and proteasome inhibitors. When Chinese hamster ovary cells that exhibit a temperature-sensitive defect in E1 ubiquitin conjugation enzyme were incubated at 40°C and 1.5% O₂, the degradation of the 1 Na,K-ATPase was prevented. Exogenous reactive oxygen species increased the plasma membrane Na,K-ATPase degradation, whereas, in mitochondrial DNA deficient ⁰ cells and in cells transfected with small interfering RNA against Rieske iron sulfur protein, the hypoxia-mediated Na,K-ATPase degradation was prevented. The catalase/superoxide dismutase (SOD) mimetic (EUK-134) and glutathione peroxidase overexpression prevented the hypoxia-mediated Na,K-ATPase degradation and overexpression of SOD1, but not SOD2, partially inhibited the Na⁺ pump degradation. Accordingly, we provide evidence that during hypoxia, mitochondrial reactive oxygen species are necessary to degrade the plasma membrane Na,K-ATPase via the ubiquitin-conjugating system.

Key Words: ATP • oxygen • proteasome • antioxidants • cell adaptation

This article has been cited by other articles:

				G. A. Gusarova, L. A. Dada, A. M. Kelly, C. Brodie, L. A. Witters, N. S. Chandel, and J. I. Sznajder {alpha}1-AMP-Activated Protein Kinase Regulates Hypoxia-Induced Na,K-ATPase Endocytosis via Direct Phosphorylation of Protein Kinase C{zeta} Mol. Cell. Biol., July 1, 2009; 29(13): 3455 - 3464. [Abstract] [Full Text] [PDF]

				C. Clerici and C. Planes Gene regulation in the adaptive process to hypoxia in lung epithelial cells Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L267 - L274. [Abstract] [Full Text] [PDF]

				A. P. Comellas, A. Briva, L. A. Dada, M. L. Butti, H. E. Trejo, C. Yshii, Z. S. Azzam, J. Litvan, J. Chen, E. Lecuona, et al. Endothelin-1 Impairs Alveolar Epithelial Function via Endothelial ETB Receptor Am. J. Respir. Crit. Care Med., January 15, 2009; 179(2): 113 - 122. [Abstract] [Full Text] [PDF]

				M. S. Reifenberger, K. L. Arnett, C. Gatto, and M. A. Milanick The reactive nitrogen species peroxynitrite is a potent inhibitor of renal Na-K-ATPase activity Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1191 - F1198. [Abstract] [Full Text] [PDF]

				G. Zhou, L. A. Dada, and J. I. Sznajder Regulation of alveolar epithelial function by hypoxia Eur. Respir. J., May 1, 2008; 31(5): 1107 - 1113. [Abstract] [Full Text] [PDF]

				G. Zhou, L. A. Dada, N. S. Chandel, K. Iwai, E. Lecuona, A. Ciechanover, and J. I. Sznajder Hypoxia-mediated Na-K-ATPase degradation requires von Hippel Lindau protein FASEB J, May 1, 2008; 22(5): 1335 - 1342. [Abstract] [Full Text] [PDF]

				L. A. Dada, E. Novoa, E. Lecuona, H. Sun, and J. I. Sznajder Role of the small GTPase RhoA in the hypoxia-induced decrease of plasma membrane Na,K-ATPase in A549 cells J. Cell Sci., July 1, 2007; 120(13): 2214 - 2222. [Abstract] [Full Text] [PDF]

				A. Dyson, R. Stidwill, V. Taylor, and M. Singer Tissue oxygen monitoring in rodent models of shock Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H526 - H533. [Abstract] [Full Text] [PDF]

				D. M. Guidot, H. G. Folkesson, L. Jain, J. I. Sznajder, J.-F. Pittet, and M. A. Matthay Integrating acute lung injury and regulation of alveolar fluid clearance Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L301 - L306. [Abstract] [Full Text] [PDF]