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)-
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.
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Metadaten
Author:Dominik Christian Fuhrmann, Ilka Wittig, Bernhard Brüne
URN:urn:nbn:de:hebis:30:3-474594
DOI:http://dx.doi.org/10.1016/j.redox.2018.10.007
ISSN:2213-2317
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=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
Pagenumber: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
Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0

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