Novel targets for ameliorating energy metabolism disorders in depression through stable isotope-resolved metabolomics

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.