Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production

The glucocorticoid receptor (GR), a nuclear receptor and major drug target, has a highly conserved minor splice variant, GR gamma, which differs by a single arginine within the DNA binding domain. GR gamma, which comprises 10% of all GR transcripts, is constitutively expressed and tightly conserved through mammalian evolution, suggesting an important non-redundant role. However, to date no specific role for GR gamma has been reported. We discovered significant differences in subcellular localisation, and nuclear-cytoplasmic shuttling in response to ligand. In addition the GR gamma transcriptome and protein interactome was distinct, and with a gene ontology signal for mitochondrial regulation which was confirmed using Seahorse technology. We propose that evolutionary conservation of the single additional arginine in GR gamma is driven by a distinct, non-redundant functional profile, including regulation of mitochondrial function.