糖皮質(zhì)激素——由腎上腺釋放進(jìn)血液中的一種激素——對于生存是至關(guān)重要的，然而延長暴露于高濃度糖皮質(zhì)激素的時(shí)間——例如在慢性應(yīng)激期間——卻能夠?qū)е掠泻Φ慕Y(jié)果,，特別是對神經(jīng)細(xì)胞尤為如此,。美國科學(xué)家如今發(fā)現(xiàn)，糖皮質(zhì)激素能夠直接影響神經(jīng)細(xì)胞中的線粒體功能,，進(jìn)而揭示了這些激素能夠影響神經(jīng)細(xì)胞功能和生存的一種機(jī)制,。
美國國立衛(wèi)生研究院（NIH）的Jing Du等研究人員在生物體外的皮質(zhì)神經(jīng)細(xì)胞中，測試了糖皮質(zhì)激素腎上腺酮對線粒體功能產(chǎn)生的生理學(xué)（低濃度）和病理生理學(xué)（高濃度）的影響,。利用低劑量腎上腺酮進(jìn)行的長期和短期處理都能夠增加線粒體氧化水平（利用一種對氧化還原反應(yīng)敏感的染料進(jìn)行評估）,，增加線粒體膜電位（利用一種陽離子染料進(jìn)行測定）,，以及增加線粒體Ca2+保持能力（通過一種Ca2+指示劑的著色進(jìn)行測量）。然而,，盡管高濃度腎上腺酮的短期處理也能夠產(chǎn)生類似的效果,，但是持續(xù)3天暴露在高濃度腎上腺酮的環(huán)境中卻能夠減弱所有三項(xiàng)線粒體功能的檢測結(jié)果。
腎上腺酮對于神經(jīng)細(xì)胞的生存也具有類似的雙向作用,。研究人員首先用高劑量或低劑量的腎上腺酮處理神經(jīng)細(xì)胞,，隨后用紅藻氨酸——能夠?qū)е录?xì)胞凋亡——與其發(fā)生反應(yīng)。結(jié)果顯示,，低劑量腎上腺酮處理1天或3天能夠增強(qiáng)神經(jīng)細(xì)胞的存活幾率,；而在這兩種時(shí)間段內(nèi)，用高劑量腎上腺酮處理卻會惡化紅藻氨酸的細(xì)胞凋亡效應(yīng),。
研究人員隨后測試了這些效應(yīng)是否與糖皮質(zhì)激素受體（GRs）從細(xì)胞溶質(zhì)到線粒體的染色體易位有關(guān),。事實(shí)上，低劑量或高劑量的腎上腺酮短期（1.5小時(shí)）處理能夠增強(qiáng)GRs的線粒體定位,。然而,，在連續(xù)3天用高劑量腎上腺酮處理后，這種染色體易位的出現(xiàn)幾率減少了,，低劑量腎上腺酮則沒有產(chǎn)生這種情況,。免疫沉淀反應(yīng)試驗(yàn)更進(jìn)一步地表明了這種關(guān)系。在線粒體中,，GRs與抗細(xì)胞凋亡蛋白質(zhì)BCL2結(jié)合在一起,。短期暴露在高劑量和低劑量的腎上腺酮下，BCL2的濃度在線粒體中得到了增加,，但連續(xù)3天暴露在高劑量腎上腺酮環(huán)境中,，BCL2的濃度則出現(xiàn)了下降。最后在活的有機(jī)體中的試驗(yàn)也證明了這一發(fā)現(xiàn)——在實(shí)驗(yàn)室小鼠體內(nèi),，腎上腺酮的慢性處理（3周時(shí)間）降低了大腦前額葉皮質(zhì)線粒體中的GR和BCL2水平,。研究人員在最近出版的美國《國家科學(xué)院院刊》上報(bào)告了這一研究成果。
總體來說,，研究人員指出,，生理學(xué)上的低糖皮質(zhì)激素水平能夠提高線粒體的功能，然而高糖皮質(zhì)激素水平最終卻會削弱這種功能,。糖皮質(zhì)激素的這種雙向作用類似于糖皮質(zhì)激素水平與海馬趾功能之間的倒U型關(guān)系,。這一發(fā)現(xiàn)表明存在一種機(jī)制,，即慢性壓力有損于神經(jīng)細(xì)胞功能和生存,，考慮到實(shí)際上所有細(xì)胞都包含有線粒體和GRs，因此它同時(shí)也會影響到其他類型的細(xì)胞,。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS February 6, 2009, doi: 10.1073/pnas.0812671106
Dynamic regulation of mitochondrial function by glucocorticoids
Jing Dua, Yun Wanga, Richard Hunterb, Yanling Weia, Rayah Blumenthala, Cynthia Falkea, Rushaniya Khairovaa, Rulun Zhoua, Peixiong Yuana, Rodrigo Machado-Vieiraa, Bruce S. McEwenb,1 and Husseini K. Manjia,1
aLaboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; and
bLaboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065
Contributed by Bruce S. McEwen, December 22, 2008 (received for review April 7, 2008)
Abstract
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.
