Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Significance

Successful response to stress requires that an organism rapidly direct its energy toward an appropriate survival response. The brain is central to successful survival decisions, and therefore its ability to allocate energetic resources precisely in response to stress is paramount. Glucocorticoid stress hormones have long been known to assist in the liberation of energy during stress via their ability to regulate the activity of the nuclear genome. The cellular powerhouse, the mitochondria, also contains a genome; herein we show that glucocorticoids, acting through their receptors, regulate the expression of mitochondrial genes in the brain. These findings demonstrate a direct molecular linkage between stress and mitochondrial function.

Abstract

Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which 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 genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has 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 NADH dehydrogenase 1, 3, and 6 ( ND-1, ND-3, ND-6) and ATP synthase 6 ( 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. 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.