Sun Ye, Li Liya, Yang Xianglong, Yin Shengming, Xiao Zhaoyang
Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027, China.
Department of Physiology, Basic Medicine College of Dalian Medical University, Dalian, 116044, China.
Transl Psychiatry. 2025 Aug 18;15(1):292. doi: 10.1038/s41398-025-03502-4.
Major depressive disorder (MDD) is characterized by persistent low mood and anhedonia. Mitochondrial dysfunction is linked to MDD, but the mechanisms are unclear. In this study, transcriptomic analysis of MDD patients' peripheral blood found three key genes: TFAM, SURF1, and NDUFB9. Single-cell transcriptomic analysis of the prefrontal cortex (PFC) in MDD patients identified seven cell types. Analysis showed strong interactions between excitatory and inhibitory neurons in the PFC, with the three genes mainly in inhibitory neurons and NDUFB9 having the highest expression. We then established a chronic unpredictable mild stress (CUMS) mouse model. CUMS exposure induced depressive-like behaviors in mice, as evidenced by decreased sucrose preference, increased immobility time in the forced swim, and reduced activity and frequency of entries into the central area in the open field. Moreover, CUMS-exposed mice exhibited mitochondrial dysfunction in the prefrontal cortex (PFC). Notably, the expressions of TFAM, SURF1, and NDUFB9 were decreased in the PFC of CUMS mice, with the most significant decrease observed in NDUFB9. Subsequently, the overexpression of NDUFB9 in CUMS-treated mice significantly alleviated depressive-like behaviors, restored mitochondrial function and reduced the death of inhibitory neurons. It also enhanced mitophagy by PINK1/Parkin pathway. Inhibiting autophagy and mitophagy confirmed mitophagy's pivotal role in NDUFB9-mediated restoration. Co-IP and protein half-life assays revealed that NDUFB9 stabilizes PINK1, thereby promoting mitophagy. In conclusion, our findings reveal a novel role of NDUFB9 on alleviating depression-like behavior by enhancing mitophagy, suggesting that targeting NDUFB9 could offer a promising therapeutic strategy for MDD.
重度抑郁症（MDD）的特征是持续的情绪低落和快感缺失。线粒体功能障碍与MDD有关，但其机制尚不清楚。在本研究中，对MDD患者外周血进行转录组分析发现了三个关键基因：TFAM、SURF1和NDUFB9。对MDD患者前额叶皮质（PFC）进行单细胞转录组分析，确定了七种细胞类型。分析显示，PFC中兴奋性和抑制性神经元之间存在强烈的相互作用，这三个基因主要存在于抑制性神经元中，且NDUFB9表达最高。然后，我们建立了慢性不可预测轻度应激（CUMS）小鼠模型。CUMS暴露诱导小鼠出现抑郁样行为，表现为蔗糖偏好降低、强迫游泳不动时间增加、旷场试验中进入中央区域的活动和频率降低。此外，CUMS暴露的小鼠前额叶皮质（PFC）出现线粒体功能障碍。值得注意的是，CUMS小鼠PFC中TFAM、SURF1和NDUFB9的表达降低，其中NDUFB9下降最为显著。随后，在CUMS处理的小鼠中过表达NDUFB9可显著减轻抑郁样行为，恢复线粒体功能并减少抑制性神经元的死亡。它还通过PINK1/Parkin途径增强线粒体自噬。抑制自噬和线粒体自噬证实了线粒体自噬在NDUFB9介导的恢复中的关键作用。免疫共沉淀和蛋白质半衰期测定表明，NDUFB9可稳定PINK1，从而促进线粒体自噬。总之，我们的研究结果揭示了NDUFB9通过增强线粒体自噬减轻抑郁样行为的新作用，表明靶向NDUFB9可能为MDD提供一种有前景的治疗策略。
