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Med Hypotheses. 2006;66(6):1205-8. Epub 2006 Jan 30.

Stress-induced change of mitochondria membrane potential regulated by genomic and non-genomic GR signaling: a possible mechanism for hippocampus atrophy in PTSD.

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Department of Psychiatry, USUHS, Bethesda, MD 20814, USA.


Posttraumatic stress disorder (PTSD) is a common psychiatric disorder often accompanied by morphologic changes in the hippocampus. Brain imaging studies have demonstrated a strong relationship between PTSD and a reduction in the volume of the hippocampus; however, the mechanisms that cause such atrophy are not well understood. In an attempt to expand our knowledge of these mechanisms, our theory has focused on the role of mitochondria in cell death, which may be associated with atrophy of the hippocampus. In addition to their function in respiration, mitochondria play an important role in the regulation of cytochrome c, an apoptotic signaling element. Normally, cytochrome c resides in the intermembrane space of mitochondria, where membrane potential exists-negative inside of about 180-200mV. In response to a variety of apoptotic stimuli, mitochondria membrane potential can be changed by genomic and non-genomic cortisol action. For the non-genomic action, stress increases cortisol levels, which activates the glucocorticoid receptor (GR). Stress-activated GR directly binds to mitochondrial membranes to regulate membrane potential. The GR will also produce a genomic action, in which GR, in interacting with several other molecules (such as heat shock proteins 90/70/40, etc.), translocates into the nucleus of the cell, where it binds to DNA and exerts transcriptional action. As one of the downstream modulaters of GR activation, Bax can be up regulated and translocated to the mitochondria, where it binds to modulator of apoptosis-1 (MAP-1), a mitochondrial effector of BAX to cause change Deltapsi. These non-genomic and genomic cortisol-induced changes of the mitochondrial membrane potential can result in the release of cytochrome c from the mitochondria to the cytoplasm where the cytochrome c promotes of the action of caspases which leads to apoptosis. Therefore, we hypothesis that stress-induced changes of mitochondrial membrane potential are regulated by non-genomic and genomic actions of cortisol in hippocampal neurons. Understanding the molecular mechanism for stress-induced cell death in the hippocampus may shed a new light on developing a mitochondrial membrane potential related therapeutic drug and/or diagnostic tool for PTSD.

[Indexed for MEDLINE]

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