Chronic Hypoxia Enhances β-Oxidation-Dependent Electron Transport via Electron Transferring Flavoproteins

Cells. 2019 Feb 18;8(2):172. doi: 10.3390/cells8020172.


Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during acute (16 h) and chronic (72 h) hypoxia, compared to normoxia, to analyze the electron flows associated with glycolysis, glutamine, and fatty acid oxidation. Oxygen consumption under acute hypoxia predominantly demanded pyruvate, while under chronic hypoxia, fatty acid- and glutamine-oxidation dominated. Chronic hypoxia also elevated electron-transferring flavoproteins (ETF), and the knockdown of ETF⁻ubiquinone oxidoreductase lowered mitochondrial respiration under chronic hypoxia. Metabolomics revealed an increase in citrate under chronic hypoxia, which implied glutamine processing to α-ketoglutarate and citrate. Expression regulation of enzymes involved in this metabolic shunting corroborated this assumption. Moreover, the expression of acetyl-CoA carboxylase 1 increased, thus pointing to fatty acid synthesis under chronic hypoxia. Cells lacking complex I, which experienced a markedly impaired respiration under normoxia, also shifted their metabolism to fatty acid-dependent synthesis and usage. Taken together, we provide evidence that chronic hypoxia fuels the ETC via ETFs, increasing fatty acid production and consumption via the glutamine-citrate-fatty acid axis.

Keywords: TMEM126B; complex I; electron transport chain; fatty acids; glutamine; mitochondria; monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia
  • Cell Respiration
  • Electron Transport
  • Electron Transport Complex I / metabolism
  • Electron-Transferring Flavoproteins / metabolism*
  • Fatty Acids / metabolism
  • Glutamine / metabolism
  • Humans
  • Iron-Sulfur Proteins / metabolism
  • Membrane Potential, Mitochondrial
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism
  • Models, Biological
  • Oxidation-Reduction
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Oxygen Consumption
  • Phenotype
  • THP-1 Cells


  • Electron-Transferring Flavoproteins
  • Fatty Acids
  • Iron-Sulfur Proteins
  • Membrane Proteins
  • TMEM126B protein, human
  • Glutamine
  • Oxidoreductases Acting on CH-NH Group Donors
  • electron-transferring-flavoprotein dehydrogenase
  • Electron Transport Complex I