TY  - JOUR
A1  - Fuhrmann, Dominik Christian
A1  - Olesch, Catherine
A1  - Kurrle, Nina Susanne
A1  - Schnütgen, Frank
A1  - Zukunft, Sven
A1  - Fleming, Ingrid
A1  - Brüne, Bernhard
T1  - Chronic hypoxia enhances β-oxidation-dependent electron transport via electron transferring flavoproteins
T2  - Cells
N2  - 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.
KW  - mitochondria
KW  - electron transport chain
KW  - complex I
KW  - TMEM126B
KW  - glutamine
KW  - fatty acids
KW  - monocytes
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/49066
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-490664
SN  - 2073-4409
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
VL  - 8
IS  - 2, Art. 172
SP  - 1
EP  - 18
PB  - MDPI
CY  - Basel
ER  -