The Ndufs4 knockout (KO) mouse is a validated and robust preclinical model of mitochondrial diseases (specifically Leigh syndrome), that displays a narrow window of relative phenotypical normality, despite its inherent mitochondrial complex I dysfunction and severe phenotype. Preclinical observations related to psychiatric comorbidities that arise in patients with mitochondrial diseases and indeed in Leigh syndrome are, however, yet to be investigated in this model. Strengthening this narrative is the fact that major depression and bipolar disorder are known to present with deficits in mitochondrial function. We therefore screened the behavioural profile of male and female Ndufs4 KO mice (relative to heterozygous; HET and wildtype; WT mice) between postnatal days 28 and 35 for locomotor, depressive- and anxiety-like alterations and linked it with selected brain biomarkers, viz. serotonin, kynurenine, and redox status in brain areas relevant to psychiatric pathologies (i.e., prefrontal cortex, hippocampus, and striatum). The Ndufs4 KO mice initially displayed depressive-like behaviour in the tail suspension test on PND31 but not on PND35 in the forced swim test. In the mirror box test, increased risk resilience was observed. Serotonin levels of KO mice, compared to HET controls, were increased on PND36, together with increased tryptophan to serotonin and kynurenine turnover. Kynurenine to kynurenic acid turnover was however decreased, while reduced versus oxidized glutathione ratio (GSH/GSSG) was increased. When considering the comorbid psychiatric traits of patients with mitochondrial disorders, this work elaborates on the neuropsychiatric profile of the Ndufs KO mouse. Secondly, despite locomotor differences, Ndufs4 KO mice present with a behavioural profile not unlike rodent models of bipolar disorder, namely variable mood states and risk-taking behaviour. The model may elucidate the bio-energetic mechanisms underlying mood disorders, especially in the presence of mitochondrial disease. Studies are however required to further validate the model's translational relevance.

Ndufs4敲除 (KO) 小鼠是一种经过验证且稳健的线粒体疾病（特别是 Leigh 综合征）临床前模型，尽管其固有的线粒体复合物I功能障碍和严重的表型，但显示出相对表型正常的狭窄窗口。然而，与线粒体疾病患者和 Leigh 综合征患者出现的精神合并症相关的临床前观察结果仍有待在该模型中进行研究。众所周知，重度抑郁症和双相情感障碍会导致线粒体功能缺陷，这一事实强化了这一说法。因此，我们筛选了雄性和雌性Ndufs4 KO 小鼠（相对于杂合子；HET 和野生型；WT 小鼠）在出生后 28 至 35 天之间的运动、抑郁和焦虑样改变的行为特征，并将其与选定的大脑生物标志物联系起来，即。与精神病理相关的大脑区域（即前额皮质、海马体和纹状体）中的血清素、犬尿氨酸和氧化还原状态。Ndufs4 KO 小鼠最初在 PND31 的悬尾测试中表现出抑郁样行为，但在强迫游泳测试中的 PND35 上却没有表现出抑郁样行为。在镜盒测试中，观察到风险抵御能力有所提高。与 HET 对照组相比，KO 小鼠的血清素水平在 PND36 上增加，同时色氨酸到血清素和犬尿氨酸的转换也增加。然而，犬尿氨酸与犬尿酸的转换减少，而还原型谷胱甘肽与氧化型谷胱甘肽的比率（GSH/GSSG）增加。在考虑线粒体疾病患者的共病精神特征时，这项工作详细阐述了Ndufs KO 小鼠的神经精神特征。其次，尽管存在运动差异，Ndufs4 KO 小鼠表现出的行为特征与双相情感障碍的啮齿动物模型没有什么不同，即可变的情绪状态和冒险行为。该模型可以阐明情绪障碍的生物能量机制，特别是在存在线粒体疾病的情况下。然而，需要进行研究来进一步验证该模型的转化相关性。