Mitochondrial dysfunction: A fatal blow in depression

Mitochondria maintain the normal physiological function of nerve cells by producing sufficient cellular energy and performing crucial roles in maintaining the metabolic balance through intracellular Ca2+ homeostasis, oxidative stress, and axonal development. Depression is a prevalent psychiatric disorder with an unclear pathophysiology. Damage to the hippocampal neurons is a key component of the plasticity regulation of synapses and plays a critical role in the mechanism of depression. There is evidence suggesting that mitochondrial dysfunction is associated with synaptic impairment. The maintenance of mitochondrial homeostasis includes quantitative maintenance and quality control of mitochondria. Mitochondrial biogenesis produces new and healthy mitochondria, and mitochondrial dynamics cooperates with mitophagy to remove damaged mitochondria. These processes maintain mitochondrial population stability and exert neuroprotective effects against early depression. In contrast, mitochondrial dysfunction is observed in various brain regions of patients with major depressive disorders. The accumulation of defective mitochondria accelerates cellular nerve dysfunction. In addition, impaired mitochondria aggravate alterations in the brain microenvironment, promoting neuroinflammation and energy depletion, thereby exacerbating the development of depression. This review summarizes the influence of mitochondrial dysfunction and the underlying molecular pathways on the pathogenesis of depression. Additionally, we discuss the maintenance of mitochondrial homeostasis as a potential therapeutic strategy for depression.