Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, China.
Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China.
Mol Psychiatry. 2023 Oct;28(10):4138-4150. doi: 10.1038/s41380-023-02098-9. Epub 2023 May 15.
Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.
抑郁症是一种常伴有能量代谢紊乱的精神疾病。抑郁症患者常出现下丘脑-垂体-肾上腺轴反应失调，糖皮质激素（GCs）释放异常。然而，GCs 与大脑能量代谢之间的相关病因仍知之甚少。在这里，我们使用代谢组学分析表明，慢性社会挫败应激（CSDS）暴露的小鼠和首发抑郁症患者的三羧酸（TCA）循环受到抑制。线粒体氧化磷酸化减少伴随着 TCA 循环的损伤。与此同时，丙酮酸脱氢酶（PDH）的活性，即线粒体 TCA 通量的守门员，被抑制，这与 CSDS 诱导的神经元丙酮酸脱氢酶激酶 2（PDK2）表达有关，进而增强了 PDH 的磷酸化。考虑到 GCs 在能量代谢中的公认作用，我们进一步证明糖皮质激素受体（GR）通过直接结合其启动子区域来刺激 PDK2 表达。同时，沉默 PDK2 可消除糖皮质激素诱导的 PDH 抑制，恢复神经元氧化磷酸化，并增加同位素标记碳（U-C]葡萄糖）进入 TCA 循环的通量。此外，在体内，GR 或 PDK2 的药理学抑制和神经元特异性沉默恢复了 CSDS 诱导的 PDH 磷酸化，并对慢性应激暴露发挥了抗抑郁作用。综上所述，我们的研究结果揭示了抑郁症表现的一种新机制，即升高的 GCs 水平通过 GR 调节 PDK2 转录，从而损害大脑能量代谢，并导致这种情况的发生。
