Endocrine Abstracts (2017) 50 S2.1 | DOI: 10.1530/endoabs.50.S2.1

Stress and direct targeting of mitochondrial gene expression by the glucocorticoid receptor in the brain

Richard Hunter1,2

1University of Massachusetts Boston, Boston, Massachusetts, USA; 2The Rockefeller University, New York, New York, USA.

Glucocorticoids (GC) are involved recruiting the energetic response to stress and act principally via the glucocorticoid receptor (GR). The GR is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular chromosome – the mitochondrial DNA (mtDNA) – that encodes 13 proteins. It has been established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of the ND-1, ND-3, ND-6 and ATP-6 genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP Sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. Further work has shown that GCs regulate mtRNA expression in a number of brain regions and peripheral tissues. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.

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