TMEM126B deficiency reduces mitochondrial SDH oxidation by LPS, attenuating HIF-1α stabilization and IL-1β expression

Area of Science:

• Cellular Biology
• Immunology
• Metabolic Biochemistry

Background:

• Mitochondrial reactive oxygen species (mtROS) play crucial roles in cellular signaling during both health and disease.
• Lipopolysaccharide (LPS) stimulation is a key trigger for inflammatory responses in macrophages.

Purpose of the Study:

• To investigate the role of mitochondrial complex I-dependent ROS signaling in LPS-stimulated macrophages.
• To identify specific targets of mtROS and their functional consequences.

Main Methods:

• Generation of THP-1 macrophages with knockdown of TMEM126B to reduce complex I assembly and mtROS production.
• BIAM switch assay coupled with liquid chromatography-mass spectrometry to identify oxidized proteins.
• Pharmacological inhibition of succinate dehydrogenase (SDH) using atpenin A5.

Main Results:

• TMEM126B knockdown attenuated mtROS production and led to reduced oxidation of SDH flavoprotein subunit A (SDHA).
• Oxidation of SDHA decreased its enzymatic activity, leading to HIF-1α stabilization and IL-1β expression.
• Pharmacological SDH inhibition restored IL-1β expression in TMEM126B knockdown cells.

Conclusions:

• mtROS directly oxidize SDH, linking altered metabolism (succinate accumulation) to inflammatory signaling.
• This pathway involves HIF-1α stabilization and subsequent IL-1β expression, highlighting a novel mechanism in macrophage inflammation.