title: Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor.
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.
authors.affiliation: Department of Psychology, University of Massachusetts, Boston, MA 02125; Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; richard.hunter@umb.edu mcewen@mail.rockefeller.edu.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Hunter
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Ma'ayan
authors.initials: M
authors.lastname: Seligsohn
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Todd G
authors.initials: TG
authors.lastname: Rubin
authors.affiliation: Department of Psychology, University of Massachusetts, Boston, MA 02125;
authors.forename: Brian B
authors.initials: BB
authors.lastname: Griffiths
authors.affiliation: Department of Psychology, University of Massachusetts, Boston, MA 02125;
authors.forename: Yildirim
authors.initials: Y
authors.lastname: Ozdemir
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065;
authors.forename: Donald W
authors.initials: DW
authors.lastname: Pfaff
authors.affiliation: Division of Medical Pharmacology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Datson
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; richard.hunter@umb.edu mcewen@mail.rockefeller.edu.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000502:physiology; D009245:NADH Dehydrogenase / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D000077278:RNA, Mitochondrial; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D011965:Receptors, Glucocorticoid; C029305:mitochondrial messenger RNA; D009245:NADH Dehydrogenase; D003345:Corticosterone
keywords: allostasis; brain metabolism; mitochondrial plasticity; mitochondrial transcription; nuclear receptors