Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-ζ
Open accessAbstract
During ascent to high altitude and pulmonary edema, the alveolar epithelial cells (AEC) are exposed to hypoxic conditions. Hypoxia inhibits alveolar fluid reabsorption and decreases Na,K-ATPase activity in AEC. We report here that exposure of AEC to hypoxia induced a time-dependent decrease of Na,K-ATPase activity and a parallel decrease in the number of Na,K-ATPase α(1) subunits at the basolateral membrane (BLM), without changing its total cell protein abundance. These effects were reversible upon reoxygenation and specific, because the plasma membrane protein GLUT1 did not decrease in response to hypoxia. Hypoxia caused an increase in mitochondrial reactive oxygen species (ROS) levels that was inhibited by antioxidants. Antioxidants prevented the hypoxia-mediated decrease in Na,K-ATPase activity and protein abundance at the BLM. Hypoxia-treated AEC deficient in mitochondrial DNA (ρ(0) cells) did not have increased levels of ROS, nor was the Na,K-ATPase activity inhibited. Na,K-ATPase α(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-ζ antagonist peptide or with the Na,K-ATPase α(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function. Accordingly, we provide evidence that hypoxia decreases Na,K-ATPase activity in AEC by triggering its endocytosis through mitochondrial ROS and PKC-ζ–mediated phosphorylation of the Na,K-ATPase α(1) subunit.
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H2O2 emission from mitochondria during hypoxia is a central upstream regulator of many cellular responses to hypoxia.
“Current evidence suggests that this H2O2 emission from mitochondria during hypoxia is a central upstream regulator of many of the cellular responses to hypoxia 8–14.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [12]
Hypoxia leads to an increase in mitochondrial production of ROS.
“Paradoxically, hypoxia leads to an increase in mitochondrial production of ROS.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [12]
PKCζ phosphorylates Na/K-ATPase α-subunits on serine-18, leading to endocytosis of the complex.
“which then phosphorylates Na/K-ATPase α-subunits on serine-18, leading to endocytosis of the complex 12.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [12]
Exposure of cells to hypoxia reversibly suppresses Na/K-ATPase activity via a mitochondrial ROS-mediated process that promotes rapid endocytosis of this protein complex.
“Exposure of cells to hypoxia reversibly suppresses Na/K-ATPase activity via a mitochondrial ROS-mediated process that promotes the rapid endocytosis of this protein complex 12.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [12]
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Self-citation
- Authors
- Dada, L. A., Chandel, N. S., Ridge, K. M., Pedemonte, C., Bertorello, A. M., & Sznajder, J. I.
- Affiliations
- Northwestern University (US)
- University of Houston (US)
- Corresponding author
- Sznajder, Jacob I.
- Venue
- Journal of Clinical Investigation
- Published
- 2003-04-01
- Volume
- 111
- Issue
- 7
- Pages
- 1057-1064
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC152585
- OpenAlex
- W2016168978
- Cited by
- 314
- References
- 34
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 20 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 13 · 2019: 4 · 2018: 5 · 2017: 10 · 2016: 20 · 2015: 17 · 2014: 5 · 2013: 14 · 2012: 18
- FWCI
- 9.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r01hl071218-01, 5r01dk053460-04)
- National Heart, Lung, and Blood Institute (HL 71218)
- National Institute of General Medical Sciences (R01GM060472, GM60472-03)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 53460)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- hypoxia, Na+/K+-ATPase, alveolar epithelial cells, endocytosis, mitochondrial reactive oxygen species, PKC zeta, protein phosphorylation, alveolar fluid reabsorption, high altitude, pulmonary edema, reoxygenation, GLUT1, mitochondrial DNA deletions
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Adenosine Triphosphate, Hypoxia, Catalase, Catalysis, Cell Membrane, Cell Survival, Endocytosis, Epithelial Cells, Humans, Hydrogen Peroxide, Microscopy, Fluorescence, Mitochondria, Mutation, Phosphorylation, Precipitin Tests, Protein Kinase C, Time Factors, Transcription Factors, Tumor Cells, Cultured, Blotting, Southern, Blotting, Western, Signal Transduction, Reactive Oxygen Species, Hypoxia-Inducible Factor 1, alpha Subunit
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