Mitochondrial Glucocorticoid Receptors and Their Actions

Abstract

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids

“…Among the large number of downregulated DEGs, it is notable the presence of genes related with GC such as FKBP5 , a cochaperone that modulates GC receptor (GR) activity, ZBTB16 , transcriptional factor contributing to energy balance after GR activation and HPGD which encondes a dehydrogenase expressed on dexamethasone (online supplemental table 31). 29–32 Accordingly, mitochondrial metabolic process characteristic of drug metabolism, specifically GC, were significantly enriched (figure 4E and online supplemental table 33). In addition, we also found enrichment in negative regulation of the type I interferon production and the innate response as well as metabolic pathways like oxidative phosphorylation or glucose metabolic process.…”

Zebrafish Mutant Lines Reveal the Interplay between nr3c1 and nr3c2 in the GC-Dependent Regulation of Gene Transcription

“…Notably, GR regulates Stat3 transcriptional activity mostly in a DNA-binding independent way, even if we cannot exclude a marginal role of canonical GR transcriptional activities in the modulation of the Jak/Stat3 pathway. Finally, it is worth mentioning that mitochondrial homeostasis is heavily regulated by GR, confirming the strong involvement of this protein in mitochondria activities [ 83 , 84 , 85 ]. Notably, the GR effect on the mitochondrial genes here analysed seems to be GR–DNA-binding independent and needs MR to be properly determined.…”

Is the glucocorticoid receptor a key player in prostate cancer?: A literature review

“…[53][54][55] In several tissues, GR activation leads to the translocation of the receptor into the mitochondria. [55][56][57][58] Six mitochondrial genome sequences show strong similarity with glucocorticoid response elements, suggesting a direct action of GR on mitochondrial transcription. [55,56,58 .…”