The severe harm of depression to human life has attracted great attention to neurologists, but its pathogenesis is extremely complicated and has not yet been fully elaborated. Here, we provided a new strategy for revealing the specific pathways of abnormal brain glucose catabolism in depression, based on the supply of energy substrates and the evaluation of the mitochondrial structure and function. By using stable isotope-resolved metabolomics, we discovered that the tricarboxylic acid cycle (TCA cycle) is blocked and gluconeogenesis is abnormally activated in chronic unpredictable mild stress (CUMS) rats. In addition, our results showed an interesting phenomenon that the brain attempted to activate all possible metabolic enzymes in energy-producing pathways, but CUMS rats still exhibited a low TCA cycle activity due to impaired mitochondria. Depression caused the mitochondrial structure and function to be impaired and then led to abnormal brain glucose catabolism. The combination of the stable isotope-resolved metabolomics and mitochondrial structure and function analysis can accurately clarify the mechanism of depression. The mitochondrial pyruvate carrier and acetyl-CoA may be the key targets for depression treatment. The strategy provides a unique insight for exploring the mechanism of depression, the discovery of new targets, and the development of ideal novel antidepressants. Data are available via ProteomeXchange with identifier PXD025548.
Keywords: brain glucose catabolism; depression; liquid chromatography-mass spectrometry; mitochondrial structure and function; stable isotope-resolved metabolomics.