Hypercapnia impairs Na,K-ATPase function by inducing endoplasmic reticulum retention of the β-subunit of the enzyme in alveolar epithelial cells

Vitalii Kryvenko, Miriam Wessendorf, Rory E. Morty, Susanne Herold, Werner Seeger, Olga Vagin, Laura A. Dada, Jacob I. Sznajder, István Vadász*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Alveolar edema, impaired alveolar fluid clearance, and elevated CO2 levels (hypercapnia) are hallmarks of the acute respiratory distress syndrome (ARDS). This study investigated how hypercapnia affects maturation of the Na,K-ATPase (NKA), a key membrane transporter, and a cell adhesion molecule involved in the resolution of alveolar edema in the endoplasmic reticulum (ER). Exposure of human alveolar epithelial cells to elevated CO2 concentrations caused a significant retention of NKA-β in the ER and, thus, decreased levels of the transporter in the Golgi apparatus. These effects were associated with a marked reduction of the plasma membrane (PM) abundance of the NKA-α/β complex as well as a decreased total and ouabain-sensitive ATPase activity. Furthermore, our study revealed that the ER-retained NKA-β subunits were only partially assembled with NKA α-subunits, which suggests that hypercapnia modifies the ER folding environment. Moreover, we observed that elevated CO2 levels decreased intracellular ATP production and increased ER protein and, particularly, NKA-β oxidation. Treatment with α-ketoglutaric acid (α-KG), which is a metabolite that has been shown to increase ATP levels and rescue mitochondrial function in hypercapnia-exposed cells, attenuated the deleterious effects of elevated CO2 concentrations and restored NKA PM abundance and function. Taken together, our findings provide new insights into the regulation of NKA in alveolar epithelial cells by elevated CO2 levels, which may lead to the development of new therapeutic approaches for patients with ARDS and hypercapnia.

Original languageEnglish (US)
Article number1467
JournalInternational journal of molecular sciences
Issue number4
StatePublished - Feb 2 2020


  • Alveolar epithelium
  • Carbon dioxide
  • Endoplasmic reticulum
  • Hypercapnia
  • Na,K-ATPase
  • Protein oxidation
  • Sodium transport

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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