Mitochondrial dysfunction in microglia: a novel perspective of depression pathogenesis

Major depressive disorder is a prevalent psychiatric disease that is closely linked to chronic low-grade neuroinflammation, which is primarily driven by microglia, the primary resident immune cells in the brain. Accumulating studies started to reveal that mitochondria, the powerhouses of the cell, play an important role in microglia-mediated neuroinflammation and neurotoxicity in depression. Stress-induced mitochondrial dysfunction triggers microglial activation through distinct mechanisms including energy metabolism patterns transition, electron transport chain impairment, reactive oxygen species accumulation, mitochondrial DNA damage, imbalanced fission and fusion, autophagy, and mitophagy deficiency, which cause the onset and progression of depression. In this review, we described microglial activation in animal models and clinically depressed patients, summarized current understanding of mitochondrial dysfunction-mediated microglial activation, and emphasized the possible mechanisms by which microglial mitochondrial dysfunction participates in the pathogenesis of depression. Understanding the roles and underlying mechanisms of mitochondrial dysfunction in neuroinflammation and neurotoxicity in depression may shed light on developing novel therapeutic strategies to fight against this devastating mental illness.