Format

Send to

Choose Destination
Cells. 2019 Feb 18;8(2). pii: E172. doi: 10.3390/cells8020172.

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

Author information

1
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
2
Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
3
German Cancer Consortium (DKTK), Partner Site, 60590 Frankfurt, Germany.
4
Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany.
5
Institute for Vascular Signaling, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
6
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany. b.bruene@biochem.uni-frankfurt.de.
7
German Cancer Consortium (DKTK), Partner Site, 60590 Frankfurt, Germany. b.bruene@biochem.uni-frankfurt.de.
8
Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany. b.bruene@biochem.uni-frankfurt.de.
9
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, 60596 Frankfurt, Germany. b.bruene@biochem.uni-frankfurt.de.

Abstract

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

PMID:
30781698
PMCID:
PMC6406996
DOI:
10.3390/cells8020172
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center