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.
Verfasserangaben: | 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 |
Titel des übergeordneten Werkes (Englisch): | Redox Biology |
Verlag: | Elsevier |
Verlagsort: | Amsterdam [u. a.] |
Dokumentart: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Jahr der Fertigstellung: | 2018 |
Datum der Erstveröffentlichung: | 19.10.2018 |
Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Datum der Freischaltung: | 06.11.2018 |
Freies Schlagwort / Tag: | BIAM-switch; Complex II; Hypoxia inducible factor; IL-1β; Mitochondrial ROS; SDH |
Jahrgang: | 20 |
Seitenzahl: | 13 |
Erste Seite: | 204 |
Letzte Seite: | 216 |
Bemerkung: | © 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 |
Institute: | Medizin / Medizin |
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs | |
DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Lizenz (Deutsch): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |