Journal
REDOX BIOLOGY
Volume 20, Issue -, Pages 204-216Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2018.10.007
Keywords
Mitochondrial ROS; Hypoxia inducible factor; BIAM-switch; Complex II; SDH; IL-1 beta
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Funding
- Deutsche Forschungsgemeinschaft, Germany [SFB815]
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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)-1 alpha and caused the subsequent, sustained expression of interleukin-1 beta (IL-1 beta). Oxidation of SDHA in sh126B cells was attenuated, while pharmacological inhibition of SDH by atpenin A5 restored IL-1 beta 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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