Stable Isotope-Resolved Metabolomics Reveals the Abnormal Brain Glucose Catabolism in Depression Based on Chronic Unpredictable Mild Stress Rats

Abstract

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.

Baicalin improves the energy levels in the prefrontal cortex of mice exposed to chronic unpredictable mild stress

“…Previous studies reported that mitochondrial function is strongly connected to depression [ 43 ]. Other researchers have reported that chronic stress can inhibit oxidative phosphorylation in mitochondria, disrupt the MMP, and damage the mitochondrial structures in various regions of mouse brains, such as the hippocampus and the prefrontal cortex [ 44 , 45 ]. In addition, disruption of the TCA cycle has been shown to reduce ATP production in a CMS-induced rat model of depression [ 46 ].…”

Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems

“…[14][15][16] Some studies revealed that CUMS can result in abnormal mitochondrial morphology, such as the mitochondrial rupture and impairment in hippocampal astrocytes, and the significant mitochondrial swelling, broken mitochondrial cristae, and decreased mitochondrial matrix density in hippocampus. 17,18 Additionally, our previous study demonstrated that the prenatal dexamethasone (Dex) exposure leads to depression-like behavior and mitochondrial damage in hippocampus, including a decrease in cristae density or even the disappearance, vacuole formation by the mitochondrial outer membrane extension, as well as the intermembrane space expansion, which can be improved by exercise. 11 Taken together, these studies corroborate the close coupling between the abnormal mitochondrial morphology and the development of depression.…”

Tryptophan-5-HT pathway disorder was uncovered in the olfactory bulb of a depression mice model by metabolomic analysis

“…Metabolomics employs liquid chromatography-mass spectrometry (LC-MS), gas chromatography (GC)-MS, and so on to analyze micromolecule of biological samples qualitatively and quantitatively for exploring the pathophysiological mechanism of life process (Ding and Mohan, 2016 ; Wishart, 2016 ). Metabolomics has been widely used to study the pathogenesis of depression (Ling-Hu et al, 2021 ; Pu et al, 2021 ). An increasing body of evidence suggests that olfactory bulb dysfunction is closely associated with depression.…”