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

Cells

Nina Kurrle¹  Frank Schnütgen¹  Ingrid Fleming²  Sven Zukunft²  Bernhard Brüne³  Catherine Olesch³  DominikC. Fuhrmann³ 

[1] Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, 60590 Frankfurt, Germany;Institute for Vascular Signaling, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany;Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany;

关键词: mitochondria;    electron transport chain;    complex I;    TMEM126B;    glutamine;    fatty acids;    monocytes;   

DOI  :  10.3390/cells8020172

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown