Dynamic regulation of mitochondrial function by glucocorticoids.
Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial function-mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity-were regulated by long-term corticosterone (CORT) treatment in an inverted "U"-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics.
Du
Jing
J
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Wang
Yun
Y
Hunter
Richard
R
Wei
Yanling
Y
Blumenthal
Rayah
R
Falke
Cynthia
C
Khairova
Rushaniya
R
Zhou
Rulun
R
Yuan
Peixiong
P
Machado-Vieira
Rodrigo
R
McEwen
Bruce S
BS
Manji
Husseini K
HK
D000818:Animals; D001692:Biological Transport; D002470:Cell Survival; D003345:Corticosterone / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D015735:Mifepristone / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D017397:Prefrontal Cortex / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques
D005938:Glucocorticoids; D019253:Proto-Oncogene Proteins c-bcl-2; D015735:Mifepristone; D003345:Corticosterone