Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications

Mitochondrial dysfunction—including DNA abnormalities, impaired energy production, disrupted quality control, and redox imbalance—is a central feature of major depressive disorder. Beyond energy deficits, mitochondria act as upstream regulators of neuroinflammation: damage-associated molecular patterns and reactive oxygen species activate innate immune signaling, and inflammation in turn compromises mitochondrial integrity. This bidirectional, self-reinforcing interaction may contribute to disease onset, progression, and clinical heterogeneity. Conventional antidepressants gradually restore mitochondrial function and suppress oxidative and inflammatory stress, while rapid-acting agents like ketamine induce acute metabolic reprogramming and mitophagy. Mitochondria-targeted antioxidants, metabolic modulators, and psychedelic compounds further highlight the therapeutic potential of targeting mitochondrial pathways.

Study at a glance

Abstract

Despite its high prevalence, the precise mechanisms underlying major depressive disorder (MDD) remain incompletely understood. Growing evidence identifies mitochondrial dysfunction, including abnormalities in mitochondrial DNA, impaired bioenergetics, disrupted quality control, and redox imbalance, as a central pathological feature of MDD. Beyond deficits in energy production, mitochondria function as upstream regulators of neuroinflammation. Mitochondria derived damage associated molecular patterns and excessive reactive oxygen species activate innate immune signaling, while inflammatory challenges in turn compromise mitochondrial integrity. This bidirectional and self-reinforcing interaction between mitochondrial dysfunction and inflammation may contribute to disease onset, progression, and clinical heterogeneity. Preclinical and clinical studies indicate that conventional antidepressants gradually restore mitochondrial function while suppressing oxidative and inflammatory stress, whereas rapid-acting agents such as ketamine induce acute metabolic reprogramming and mitophagy, enabling swift functional recovery. Mechanistically distinct interventions, including mitochondria targeted antioxidants, metabolic modulators, and psychedelic compounds, further highlight the therapeutic potential of targeting mitochondrial pathways. By integrating current evidence, this review delineates mitochondrial-inflammation crosstalk in MDD and supports mitochondrial regulation as a promising target for novel antidepressant strategies.