Research Shows How Chronic Stress May be Linked to Physical and Mental Ailments

February 3, 2009 • Science Update

While scientists have long known that the levels of certain hormones rise in response to chronic stress, an NIMH study is the first to describe a potential fundamental mechanism for this process. Published in the February 2, 2009 issue of the Proceedings of the National Academy of Sciences, the findings reveal how individual cells adapt to cope with sudden or extreme stress, and how repeated exposure to stress may be related to many physical and mental illnesses.

Cortisol, a type of hormone called a glucocorticoid, plays a key role in the human brain's ability to adapt and recover from injury. It also plays a part in getting hormone receptors to the right places, where brain chemicals exert their effects.

In rats, corticosterone acts the same way as cortisol does in humans. Recent rat studies suggest that glucocorticoid receptors (GRs) move into mitochondria, energy-producing structures inside cells, in response to corticosterone. However, the research has not previously shown how this process occurred, or how it may affect mitochondrial or overall cell function.

Jing Du, M.D., Ph.D., of the NIMH Mood and Anxiety Disorders Program (MAP), along with Husseini Manji, M.D., former director of MAP, and colleagues found that in brain cells of rats treated with corticosterone, GR latched onto Bcl-2, a protein that affects how substances get in and out of mitochondria. The GR/Bcl-2 complex moves into the mitochondria and regulates mitochondrial functions.

Brief increases of corticosterone enhance mitochondrial functions. However, the researchers found that high doses or long-term treatment with corticosterone led to decreased levels of GR and Bcl-2 in mitochondria. Similar results occur in rats exposed to chronic stress.

The study results show that, at first, glucocorticoids like cortisol or corticosterone boost mitochondrial functions to provide cells with more energy for coping with and adapting to acute challenges. This process appears to be critical in allowing a person to act quickly in an emergency.

However, chronic stress may lead to chronically elevated levels of glucocorticoids, which in turn may reduce cell functioning, via the interaction between GR/Bcl-2 and mitochondria. The decrease in proper cell function may be at the root of certain physical and mental illnesses.

This finding may be relevant to research on a number of stress-related illnesses, including anxiety disorders, depression, and post-traumatic stress disorder (PTSD), and suggests new pathways for improving treatments.

Reference

Du J, Wang Y, Hunter R, Wei Y, Blumenthal R, Falke C, Khairova R, Zhou R, Yuan P, Machado-Vieira R, McEwen BS, Manji HK. Dynamic regulation of mitochondrial function by glucocorticoids . Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3543-8. Epub 2009 Feb 6. PubMed PMID: 19202080; PubMed Central PMCID: PMC2637276.