Pterosin B has multiple targets in gluconeogenic programs, including coenzyme Q in RORα-SRC2 signaling

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Metabolism

Background:

• Hepatic gluconeogenesis is crucial for glucose homeostasis and regulated by signaling cascades like glucagon-cAMP.
• Glucose-6-phosphatase catalytic subunit (G6pc) is a key enzyme in gluconeogenesis.
• Pterosin B from Pteridium aquilinum influences gluconeogenic gene expression via salt-inducible kinase 3 and CREB-regulated transcription coactivator 2.

Purpose of the Study:

• To investigate the paradoxical effect of Pterosin B on G6pc expression under cAMP signaling.
• To identify the molecular targets of Pterosin B in regulating gluconeogenic programs.
• To explore the link between mitochondrial oxidative phosphorylation (OXPHOS) and G6pc regulation.

Main Methods:

• Investigated Pterosin B's effect on G6pc expression in the presence and absence of cAMP.
• Identified transcription factors interacting with Pterosin B using chromatin immunoprecipitation assays.
• Assessed the impact of Pterosin B and OXPHOS inhibitors on the RORα-SRC2 complex and coenzyme Q oxidation-reduction cycle.

Main Results:

• Pterosin B initially promoted G6pc expression but strongly repressed it upon cAMP activation.
• The retinoic acid receptor-related orphan receptor alpha-steroid receptor coactivator 2 (RORα-SRC2) complex on the G6pc promoter was identified as a key target of Pterosin B.
• Pterosin B impaired the coenzyme Q oxidation-reduction cycle in OXPHOS, mimicking antimycin A's effect on RORα-SRC2 signaling.

Conclusions:

• The RORα-SRC2 complex acts as a sensor for the coenzyme Q oxidation-reduction cycle, regulating G6pc expression in hepatic gluconeogenic programs.
• Pterosin B disrupts this sensor mechanism, providing a novel insight into the regulation of gluconeogenesis.
• Mitochondrial OXPHOS components differentially influence transcriptional regulation of gluconeogenic programs.