Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications
Yu Wang, Ji-tao Li, Lin-lin Zhu, Yan-kun Wu, Yun-ai Su, Tian-mei Si
Molecular Psychiatry July 3, 2026 Peer reviewed DOI: 10.1038/s41380-026-03732-y via Springer Nature
Summary
Mitochondrial dysfunction plays a key role in major depressive disorder (MDD), involving issues like mitochondrial DNA abnormalities and disrupted energy production, which contribute to neuroinflammation. Conventional antidepressants can gradually restore mitochondrial function, while rapid-acting treatments like ketamine provide quick recovery through metabolic changes. The interplay between mitochondrial dysfunction and inflammation may influence the onset and progression of MDD, suggesting that targeting these pathways could lead to new treatment strategies.
Study at a glance
| Design | review |
|---|---|
| Key finding | The review highlights the importance of mitochondrial-inflammation interactions in MDD and suggests that targeting mitochondrial pathways could be a promising approach for developing new antidepressant treatments. |
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.