Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications
Molecular Psychiatry July 3, 2026 Yu Wang, Ji-Tao Li, Lin-Lin Zhu et al.
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.