TMEM126B deficiency reduces mitochondrial SDH oxidation by LPS, attenuating HIF-1α stabilization and IL-1β expression
- Mitochondrial derived reactive oxygen species (mtROS) are known for their signaling qualities in both physiology and pathology. To elucidate mitochondrial complex I-dependent ROS-signaling after lipopolysaccharide (LPS)-stimulation THP-1 macrophages with a knockdown of the transmembrane protein TMEM126B were generated. TMEM knockdown cells (sh126B) showed a reduced assembly of complex I and attenuated mtROS production. In these cells we identified protein oxidization by mtROS upon LPS-treatment using the BIAM switch assay coupled to liquid chromatography and mass spectrometry. One of the identified targets of mtROS was succinate dehydrogenase (SDH) flavoprotein subunit A (SDHA). Oxidation of SDHA decreased its enzymatic activity and pharmacological inhibition of SDH in turn stabilized hypoxia inducible factor (HIF)-1α and caused the subsequent, sustained expression of interleukin-1β (IL-1β). Oxidation of SDHA in sh126B cells was attenuated, while pharmacological inhibition of SDH by atpenin A5 restored IL-1β expression in sh126B cells upon LPS-treatment. Conclusively, oxidation of SDH by mtROS links an altered metabolism, i.e. succinate accumulation to HIF-1-driven, inflammatory changes in macrophages.
Author: | Dominik Christian FuhrmannORCiDGND, Ilka WittigORCiD, Bernhard BrüneORCiD |
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URN: | urn:nbn:de:hebis:30:3-474594 |
DOI: | https://doi.org/10.1016/j.redox.2018.10.007 |
ISSN: | 2213-2317 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/30368040 |
Parent Title (English): | Redox Biology |
Publisher: | Elsevier |
Place of publication: | Amsterdam [u. a.] |
Document Type: | Article |
Language: | English |
Year of Completion: | 2018 |
Date of first Publication: | 2018/10/19 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2018/11/06 |
Tag: | BIAM-switch; Complex II; Hypoxia inducible factor; IL-1β; Mitochondrial ROS; SDH |
Volume: | 20 |
Page Number: | 13 |
First Page: | 204 |
Last Page: | 216 |
Note: | © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). |
HeBIS-PPN: | 440087066 |
Institutes: | Medizin / Medizin |
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs | |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |