College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310032, China.
Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
J Steroid Biochem Mol Biol. 2020 Jun;200:105607. doi: 10.1016/j.jsbmb.2020.105607. Epub 2020 Feb 8.
Stress exerts its negative effects by interference with mitochondrial energy production in rodents, and is able to impair mitochondrial bioenergetics. However, the underlying mechanism that stress hormone impacts depression-like behaviors and mitochondrial energy metabolism is still not well understood. Here, we investigated the changes of depression-like behaviors and mitochondrial energy metabolism induced by chronic corticosterone (CORT). The results showed that after treatment with CORT for 6 weeks, mice displayed depression-like behaviors, which were identified by tail suspension test, forced swimming test and open field test. Then, the livers were isolated and tested by RNA sequencing and metabolome analysis. RNA sequencing showed 354 up-regulated genes and 284 down-regulated genes, and metabolome analysis revealed 280 metabolites with increased abundances and 193 metabolites with reduced abundances in the liver of mice after CORT, which were closely associated with lipid metabolism and oxidative phosphorylation in mitochondria. Based on these findings, the changes of mitochondrial energy metabolism were investigated, and we revealed that CORT condition inhibited glycolysis and fatty acid degradation pathway, and activated synthesis of triacylglycerol, leading to the reduced levels of acetyl-CoA and attenuated TCA cycle. Also, the pathways of NAD synthesis were inhibited, resulting in the reduced activity of sirtuin 3 (SIRT3). Thus, all of these observations disrupted the function of mitochondria, and led to the decrease of ATP production. Our findings uncover a novel mechanism of stress on depression-like behaviors and mitochondrial energy metabolism in rodents.
压力通过干扰啮齿动物线粒体的能量产生来产生负面影响，并能够损害线粒体生物能。然而，应激激素如何影响抑郁样行为和线粒体能量代谢的潜在机制仍不清楚。在这里，我们研究了慢性皮质酮（CORT）诱导的抑郁样行为和线粒体能量代谢的变化。结果表明，经过 6 周 CORT 处理后，小鼠表现出抑郁样行为，通过悬尾试验、强迫游泳试验和旷场试验来识别。然后，分离肝脏并通过 RNA 测序和代谢组分析进行测试。RNA 测序显示 354 个上调基因和 284 个下调基因，代谢组分析显示 CORT 后小鼠肝脏中 280 种代谢物丰度增加，193 种代谢物丰度降低，与脂质代谢和线粒体氧化磷酸化密切相关。基于这些发现，我们研究了线粒体能量代谢的变化，结果表明 CORT 条件抑制了糖酵解和脂肪酸降解途径，并激活了三酰甘油的合成，导致乙酰辅酶 A 水平降低和 TCA 循环减弱。此外，NAD 合成途径受到抑制，导致 SIRT3 的活性降低。因此，所有这些观察结果都破坏了线粒体的功能，导致 ATP 产生减少。我们的研究结果揭示了压力对啮齿动物抑郁样行为和线粒体能量代谢的新机制。
