Modern Research Center for Traditional Chinese Medicine, the Institute for Biomedicine and Health, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, the Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Shanxi University, Taiyuan 030006, China.
Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, China.
Biochim Biophys Acta Bioenerg. 2022 Oct 1;1863(7):148578. doi: 10.1016/j.bbabio.2022.148578. Epub 2022 May 28.
The severe harm of depression to human health and life has attracted global attention, but the exact mechanism is not yet known due to the complicated pathogenesis. The existing antidepressants are far from ideal, indicating it is urgently needed to seek safe and effective drugs from a unique perspective. Based on the hypothesis of "mitochondrial dysfunction" proposed recently, we attempt to focus on the substrates supply of energy metabolism. We applied stable isotope-resolved metabolomics, and revealed that significantly decreased TCA cycle and abnormally increased gluconeogenesis pathway in CUMS rats. Pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) maybe the key metabolic enzymes. This metabolic reprogramming was confirmed through ELISA assays and Western blot analysis. To explore the causes of substrates supply disorder in depression, we conducted the mitochondrial structure-function evaluation. Interestingly, the levels of the mitochondrial pyruvate carrier (MPC) decreased significantly, which is essential for the entry of pyruvic acid into the TCA cycle. Together, MPC, PDH and PC are expected to become potential novel therapeutic targets for treating depressive disorders. This research provides a unique insight for re-cognizing the pathological mechanisms of depression, the novel targets for development of ideal antidepressants, as well as a paradigm for deciphering abnormal metabolic pathways in other metabolic diseases.
抑郁症对人类健康和生命的严重危害引起了全球关注，但由于发病机制复杂，其确切机制尚不清楚。现有的抗抑郁药远非理想，这表明急需从独特的角度寻找安全有效的药物。基于最近提出的“线粒体功能障碍”假说，我们试图专注于能量代谢的底物供应。我们应用稳定同位素解析代谢组学，揭示了 CUMS 大鼠中 TCA 循环显著减少和糖异生途径异常增加。丙酮酸脱氢酶（PDH）和丙酮酸羧化酶（PC）可能是关键的代谢酶。通过 ELISA 测定和 Western blot 分析证实了这种代谢重编程。为了探讨抑郁症底物供应紊乱的原因，我们进行了线粒体结构-功能评估。有趣的是，线粒体丙酮酸载体（MPC）的水平显著降低，这对于丙酮酸进入 TCA 循环是必不可少的。总之，MPC、PDH 和 PC 有望成为治疗抑郁症的潜在新型治疗靶点。这项研究为重新认识抑郁症的病理机制、开发理想抗抑郁药的新靶点以及解析其他代谢性疾病异常代谢途径提供了独特的视角。
