Mitochondrial metabolic reprogramming of microglia in neuroinflammation: Implications for major depressive disorder

Major depressive disorder (MDD) is a recurrent episodic mood disorder characterized by persistent low mood and loss of interest. The pathogenesis of major depressive disorder (MDD) involves a neuroinflammatory response, neurotransmitter dysfunction, blood-brain barrier disruption, oxidative stress, and mitochondrial dysfunction. Neuroinflammation, caused by the overactivation of microglia, is considered a key factor in the development of the disease. Metabolic reprogramming has been shown to play a crucial role in microglial activation and executive function. In MDD, microglia have the potential to become activated and transform into either pro-inflammatory or anti-inflammatory phenotypes. These variations in cellular phenotypes lead to differences in cellular energy metabolism. Mitochondria are involved in the energy metabolism of microglia and have intricate connections with microglia-mediated metabolic reprogramming and neuroinflammation. However, the specific changes in the metabolic reprogramming of microglia in depression, the numerous signaling pathways and cytokines involved, and the mechanisms by which they mediate phenotypic transitions remain unclear. Therefore, this review summarizes the metabolic reprogramming of microglia in MDD, as well as the involved signaling pathways, mitochondrial involvement and cytokines, and elaborates on their interaction with phenotypic transformation. The effects of drugs on regulating immune metabolic reprogramming to suppress neuroinflammation were summarized, providing potential for new research approaches in the treatment of MDD.