Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production

Area of Science:

• Molecular Biology
• Cell Biology
• Genomics

Background:

• The glucocorticoid receptor (GR) is a key nuclear receptor and drug target.
• A minor splice variant, GRγ, is highly conserved across mammals, comprising 10% of GR transcripts.
• Despite its conservation and expression, GRγ's specific function remained unknown.

Purpose of the Study:

• To investigate the distinct functional role of the GRγ splice variant.
• To explore differences in subcellular localization, ligand response, and molecular interactions of GRγ compared to canonical GR.
• To determine if GRγ plays a role in cellular metabolic regulation.

Main Methods:

• Comparative analysis of GRγ and GR subcellular localization and nuclear-cytoplasmic shuttling.
• Transcriptome and proteome analysis to identify GRγ-specific targets and interactors.
• Seahorse technology to assess mitochondrial function in relation to GRγ activity.

Main Results:

• GRγ exhibits distinct subcellular localization and differential nuclear-cytoplasmic shuttling upon ligand binding.
• GRγ possesses a unique transcriptome and protein interactome.
• Gene ontology analysis revealed a significant signal for mitochondrial regulation, confirmed by experimental data.

Conclusions:

• The evolutionary conservation of GRγ is attributed to its distinct, non-redundant functions.
• GRγ plays a significant role in regulating mitochondrial function.
• GRγ represents a novel functional entity within the glucocorticoid receptor signaling pathway.