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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    175—Cellular Actions of Stress

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    175.07: Stress and corticosterone regulate rat hippocampal mitochondrial chromosome gene expression via the glucocorticoid receptor

    Location: Halls B-H

    ">*R. G. HUNTER1,2,3, M. SELIGSOHN4, T. RUBIN2, N. A. DATSON5, D. W. PFAFF3, B. S. MCEWEN2;
    1Psychology, Univ. of Massachusetts, Boston, Boston, MA; 2Lab. of Neuroendocrinology, 3Lab. of Neurobio. and Behavior, 42-Laboratory of Neuroendocrinology, The Rockefeller Univ., New York, NY; 5Div. of Med. Pharmacol., Leiden Univ. Med. Ctr., Leiden, Netherlands

    Abstract Body: Steroid receptors have long been known to regulate the expression of the nuclear genome and recent findings have shown that they have the capacity to alter mitochondrial function. Here we show that acute and chronic restraint stress regulate the expression of mitochondrial genes in the rat hippocampus, most significantly ND-6, which codes for a subunit of complex I. There was a main effect of acute stress on overall mitochondrial transcription and ND-6, ND-1 and ATP-6 mRNA expression were all significantly decreased by acute stress, while ND-6 levels increased after 21 days of chronic restraint. Further, adrenalectomy prevents the down regulation of mtRNA expression due to acute stress and in fact significantly increases it. Lastly we show, using ChIP-Seq that corticosterone administration increases the binding of the glucocorticoid receptor to the mitochondrial genome. Taken together these findings demonstrate that stress and adrenal steroids have the capacity to directly control the brain mitochondrial transcriptome, a finding with significant implications for a variety of brain disorders where mitochondrial dysfunction has been implicated.

    Lay Language Summary: Our research has shown that the receptor for the stress hormone corticosterone, the glucocorticoid receptor, interacts directly with the DNA of the cell powerhouse, the mitochondria, in the brain, to control its activity. Further we show that a single, acute stress has a markedly different effect on mitochondrial gene expression than repeated stress.
    Stress is a factor in many of the complex diseases that effect modern man, such as diabetes, cardiovascular disease and major depression. Stress increases the levels of stress hormones like corticosterone. Corticosterone in turn binds to receptors called glucocorticoid receptors (GR), causing them to activate and bind to DNA in the nucleus of a variety of cells, including the neurons in brain regions like the hippocampus. The hippocampus is responsible for the formation of long term memories and for social and spatial processing. Due to the high expression of GR in the hippocampus, it is highly sensitive to stress and its size and function can be reduced by chronic stress, depression and other disorders.
    The brain consumes roughly 10 times more energy relative to its size than other tissues, and most of this energy is generated in the cellular organelle known as the mitochondria. The mitochondria are unique in mammalian cells because they have their own DNA, separate from the DNA in the nucleus. This is due to their origin as separate organisms which entered into symbiosis with eukaryotic cells, like our own, deep in the evolutionary past. In addition to their role as cellular powerhouse, the mitochondria are also the key to the cellular self-destruct mechanism. These properties have linked mitochondria to a variety of neurodegenerative disorders including Parkinson’s and Alzheimer’s disease.
    To determine the effects of stress on mitochondrial gene expression in the hippocampus we subjected male rats to either a single, 30 minute, acute stress, or to 3 weeks of repeated stress and then examined the expression of mitochondrial genes (mt genes). We found that acute stress reduced the overall expression of mitochondrial genes, most notably the ND-6 gene. Repeated stress, in contrast, had little effect on most of the mitochondrial genes, except ND-6, which showed a substantial increase in expression.

    To demonstrate that corticosterone was responsible for this effect we removed the adrenal glands, the source of the hormone, and examined the effect of this surgery on the expression of mt genes under normal and acute stress conditions. We found that in the absence of corticosterone there was a substantial increase in the expression of a number of mt genes and that acute stress was no longer able to decrease the level of mt gene expression.
    In order to conclusively demonstrate that the GR was binding to the mitochondrial DNA, we performed ChIP sequencing to determine if and where the GR bound to the mt genome in the presence or absence of corticosterone. We found that corticosterone causes the GR to bind to the mt genome in the vicinity of the
    ND-6 gene, perhaps explaining why this particular gene showed the largest changes in gene expression with stress.
    Stress clearly has an effect on the function of brain mitochondria, even down to the level of mitochondrial genes. This finding has substantial implications for a number of brain diseases and for our understanding of the physiological impact of uncontrollable stress in our lives.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    175—Cellular Actions of Stress

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    175.07: Stress and corticosterone regulate rat hippocampal mitochondrial chromosome gene expression via the glucocorticoid receptor

    Location: Halls B-H

    ">*R. G. HUNTER1,2,3, M. SELIGSOHN4, T. RUBIN2, N. A. DATSON5, D. W. PFAFF3, B. S. MCEWEN2;
    1Psychology, Univ. of Massachusetts, Boston, Boston, MA; 2Lab. of Neuroendocrinology, 3Lab. of Neurobio. and Behavior, 42-Laboratory of Neuroendocrinology, The Rockefeller Univ., New York, NY; 5Div. of Med. Pharmacol., Leiden Univ. Med. Ctr., Leiden, Netherlands

    Abstract Body: Steroid receptors have long been known to regulate the expression of the nuclear genome and recent findings have shown that they have the capacity to alter mitochondrial function. Here we show that acute and chronic restraint stress regulate the expression of mitochondrial genes in the rat hippocampus, most significantly ND-6, which codes for a subunit of complex I. There was a main effect of acute stress on overall mitochondrial transcription and ND-6, ND-1 and ATP-6 mRNA expression were all significantly decreased by acute stress, while ND-6 levels increased after 21 days of chronic restraint. Further, adrenalectomy prevents the down regulation of mtRNA expression due to acute stress and in fact significantly increases it. Lastly we show, using ChIP-Seq that corticosterone administration increases the binding of the glucocorticoid receptor to the mitochondrial genome. Taken together these findings demonstrate that stress and adrenal steroids have the capacity to directly control the brain mitochondrial transcriptome, a finding with significant implications for a variety of brain disorders where mitochondrial dysfunction has been implicated.

    Lay Language Summary: Our research has shown that the receptor for the stress hormone corticosterone, the glucocorticoid receptor, interacts directly with the DNA of the cell powerhouse, the mitochondria, in the brain, to control its activity. Further we show that a single, acute stress has a markedly different effect on mitochondrial gene expression than repeated stress.
    Stress is a factor in many of the complex diseases that effect modern man, such as diabetes, cardiovascular disease and major depression. Stress increases the levels of stress hormones like corticosterone. Corticosterone in turn binds to receptors called glucocorticoid receptors (GR), causing them to activate and bind to DNA in the nucleus of a variety of cells, including the neurons in brain regions like the hippocampus. The hippocampus is responsible for the formation of long term memories and for social and spatial processing. Due to the high expression of GR in the hippocampus, it is highly sensitive to stress and its size and function can be reduced by chronic stress, depression and other disorders.
    The brain consumes roughly 10 times more energy relative to its size than other tissues, and most of this energy is generated in the cellular organelle known as the mitochondria. The mitochondria are unique in mammalian cells because they have their own DNA, separate from the DNA in the nucleus. This is due to their origin as separate organisms which entered into symbiosis with eukaryotic cells, like our own, deep in the evolutionary past. In addition to their role as cellular powerhouse, the mitochondria are also the key to the cellular self-destruct mechanism. These properties have linked mitochondria to a variety of neurodegenerative disorders including Parkinson’s and Alzheimer’s disease.
    To determine the effects of stress on mitochondrial gene expression in the hippocampus we subjected male rats to either a single, 30 minute, acute stress, or to 3 weeks of repeated stress and then examined the expression of mitochondrial genes (mt genes). We found that acute stress reduced the overall expression of mitochondrial genes, most notably the ND-6 gene. Repeated stress, in contrast, had little effect on most of the mitochondrial genes, except ND-6, which showed a substantial increase in expression.

    To demonstrate that corticosterone was responsible for this effect we removed the adrenal glands, the source of the hormone, and examined the effect of this surgery on the expression of mt genes under normal and acute stress conditions. We found that in the absence of corticosterone there was a substantial increase in the expression of a number of mt genes and that acute stress was no longer able to decrease the level of mt gene expression.
    In order to conclusively demonstrate that the GR was binding to the mitochondrial DNA, we performed ChIP sequencing to determine if and where the GR bound to the mt genome in the presence or absence of corticosterone. We found that corticosterone causes the GR to bind to the mt genome in the vicinity of the
    ND-6 gene, perhaps explaining why this particular gene showed the largest changes in gene expression with stress.
    Stress clearly has an effect on the function of brain mitochondria, even down to the level of mitochondrial genes. This finding has substantial implications for a number of brain diseases and for our understanding of the physiological impact of uncontrollable stress in our lives.