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.

中文翻译：

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抑郁样行为伴随着慢性皮质酮诱导的小鼠线粒体能量代谢的破坏。

应力通过干扰啮齿动物的线粒体能量产生而发挥其负面作用，并且能够损害线粒体的生物能。然而，应激激素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CORT处理6周后，小鼠表现出抑郁样行为，这可通过尾部悬吊试验，强迫游泳试验和野外试验来鉴定。然后，分离肝脏并通过RNA测序和代谢组学分析进行测试。RNA测序显示354个上调基因和284个下调基因，代谢组学分析表明，CORT后小鼠肝脏中280种代谢物含量增加，而193种代谢物含量降低，这与脂质代谢和线粒体的氧化磷酸化密切相关。基于这些发现，研究了线粒体能量代谢的变化，我们发现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，从而导致乙酰辅酶A水平降低和TCA周期降低。此外，NAD +合成的途径受到抑制，导致Sirtuin 3（SIRT3）的活性降低。因此，所有这些观察结果破坏了线粒体的功能，并导致ATP产生的减少。