α1-AMP-Activated Protein Kinase Regulates Hypoxia-Induced Na,K-ATPase Endocytosis via Direct Phosphorylation of Protein Kinase Cζ
Open accessAbstract
Hypoxia promotes Na,K-ATPase endocytosis via protein kinase C zeta (PKC zeta)-mediated phosphorylation of the Na,K-ATPase alpha subunit. Here, we report that hypoxia leads to the phosphorylation of 5'-AMP-activated protein kinase (AMPK) at Thr172 in rat alveolar epithelial cells. The overexpression of a dominant-negative AMPK alpha subunit (AMPK-DN) construct prevented the hypoxia-induced endocytosis of Na,K-ATPase. The overexpression of the reactive oxygen species (ROS) scavenger catalase prevented hypoxia-induced AMPK activation. Moreover, hypoxia failed to activate AMPK in mitochondrion-deficient rho(0)-A549 cells, suggesting that mitochondrial ROS play an essential role in hypoxia-induced AMPK activation. Hypoxia-induced PKC zeta translocation to the plasma membrane and phosphorylation at Thr410 were prevented by the pharmacological inhibition of AMPK or by the overexpression of the AMPK-DN construct. We found that AMPK alpha phosphorylates PKC zeta on residue Thr410 within the PKC zeta activation loop. Importantly, the activation of AMPK alpha was necessary for hypoxia-induced AMPK-PKC zeta binding in alveolar epithelial cells. The overexpression of T410A mutant PKC zeta prevented hypoxia-induced Na,K-ATPase endocytosis, confirming that PKC zeta Thr410 phosphorylation is essential for this process. PKC zeta activation by AMPK is isoform specific, as small interfering RNA targeting the alpha1 but not the alpha2 catalytic subunit prevented PKC zeta activation. Accordingly, we provide the first evidence that hypoxia-generated mitochondrial ROS lead to the activation of the AMPK alpha1 isoform, which binds and directly phosphorylates PKC zeta at Thr410, thereby promoting Na,K-ATPase endocytosis.
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Hypoxia-induced Na/K-ATPase endocytosis requires the activity of AMP-activated protein kinase.
“Hypoxia-induced Na/K-ATPase endocytosis requires the activity of AMP-activated protein kinase (AMPK) 23.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [23]
During hypoxia, AMPK phosphorylates and activates protein kinase C zeta.
“During hypoxia, AMPK phosphorylates and activates protein kinase C zeta (PKCζ) 23”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [23]
Mitochondrial ROS production triggers AMPK activation during hypoxia.
“Mitochondrial ROS production triggers AMPK activation during hypoxia, providing a link between ROS and Na/K-ATPase inhibition 13, 23.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [23]
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- Authors
- Gusarova, G. A., Dada, L. A., Kelly, A. M., Brodie, C., Witters, L. A., Chandel, N. S., & Sznajder, J. I.
- Affiliations
- Northwestern University (US)
- Henry Ford Health (US)
- Dartmouth College (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-07-01
- Volume
- 29
- Issue
- 13
- Pages
- 3455-3464
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2698765
- OpenAlex
- W2105076167
- Cited by
- 118
- References
- 45
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 12 · 2020: 4 · 2019: 7 · 2018: 4 · 2017: 8 · 2016: 6 · 2015: 9 · 2014: 3 · 2013: 11 · 2012: 14
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL-071643)
- National Heart, Lung, and Blood Institute (HL093014, P01HL071643, R01HL093014)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- 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
- AMPK, protein kinase C zeta, hypoxia, mitochondrial reactive oxygen species, alveolar epithelial cells, catalase, isoform specificity
- MeSH terms
- Protein Kinase C zeta, Sodium-Potassium-Exchanging ATPase, Animals, Hypoxia, Endocytosis, Enzyme Activation, Epithelial Cells, Humans, Isoenzymes, Mitochondria, Phosphorylation, Protein Kinase C, Pulmonary Alveoli, Signal Transduction, Rats, Sprague-Dawley, Reactive Oxygen Species, RNA, Small Interfering, Rats, AMP-Activated Protein Kinases
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