Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production

Sci Rep. 2016 May 26:6:26419. doi: 10.1038/srep26419.


The glucocorticoid receptor (GR), a nuclear receptor and major drug target, has a highly conserved minor splice variant, GRγ, which differs by a single arginine within the DNA binding domain. GRγ, 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 GRγ has been reported. We discovered significant differences in subcellular localisation, and nuclear-cytoplasmic shuttling in response to ligand. In addition the GRγ 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 GRγ is driven by a distinct, non-redundant functional profile, including regulation of mitochondrial function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenosine Triphosphate / metabolism*
  • Cell Nucleus / metabolism
  • Cytoplasm
  • Evolution, Molecular
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • HEK293 Cells
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Models, Molecular
  • Protein Binding
  • Proteomics
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / metabolism*


  • GRgamma protein, human
  • Receptors, Glucocorticoid
  • Adenosine Triphosphate