Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom, South Africa.
Institut de Neurociències i Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, Barcelona, Spain.
Mol Neurobiol. 2021 Jan;58(1):243-262. doi: 10.1007/s12035-020-02121-y. Epub 2020 Sep 11.
Mitochondrial diseases (MD), such as Leigh syndrome (LS), present with severe neurological and muscular phenotypes in patients, but have no known cure and limited treatment options. Based on their neuroprotective effects against other neurodegenerative diseases in vivo and their positive impact as an antioxidant against complex I deficiency in vitro, we investigated the potential protective effect of metallothioneins (MTs) in an Ndufs4 knockout mouse model (with a very similar phenotype to LS) crossed with an Mt1 overexpressing mouse model (TgMt1). Despite subtle reductions in the expression of neuroinflammatory markers GFAP and IBA1 in the vestibular nucleus and hippocampus, we found no improvement in survival, growth, locomotor activity, balance, or motor coordination in the Mt1 overexpressing Ndufs4 mice. Furthermore, at a cellular level, no differences were detected in the metabolomics profile or gene expression of selected one-carbon metabolism and oxidative stress genes, performed in the brain and quadriceps, nor in the ROS levels of macrophages derived from these mice. Considering these outcomes, we conclude that MT1, in general, does not protect against the impaired motor activity or improve survival in these complex I-deficient mice. The unexpected absence of increased oxidative stress and metabolic redox imbalance in this MD model may explain these observations. However, tissue-specific observations such as the mildly reduced inflammation in the hippocampus and vestibular nucleus, as well as differential MT1 expression in these tissues, may yet reveal a tissue- or cell-specific role for MTs in these mice.
线粒体疾病（MD），如 Leigh 综合征（LS），在患者中表现出严重的神经和肌肉表型，但目前尚无已知的治疗方法，且治疗选择有限。基于其在体内对其他神经退行性疾病的神经保护作用，以及在体外作为抗氧化剂对复合物 I 缺乏症的积极影响，我们研究了金属硫蛋白（MTs）在 Ndufs4 敲除小鼠模型（与 LS 非常相似的表型）与过表达 Mt1 的小鼠模型（TgMt1）交叉时的潜在保护作用。尽管在 vestibular nucleus 和 hippocampus 中的神经炎症标志物 GFAP 和 IBA1 的表达略有降低，但我们发现过表达 Mt1 的 Ndufs4 小鼠的存活率、生长、运动活动、平衡或运动协调能力没有改善。此外，在细胞水平上，在大脑和四头肌中进行的选定一碳代谢和氧化应激基因的代谢组学图谱或基因表达，以及这些小鼠来源的巨噬细胞的 ROS 水平，均未检测到差异。考虑到这些结果，我们得出结论，一般来说，MT1 不能防止这些复合物 I 缺乏小鼠运动活动受损或提高存活率。在这种 MD 模型中，出乎意料的是没有增加氧化应激和代谢氧化还原失衡，这可能解释了这些观察结果。然而，组织特异性观察，如海马体和前庭神经核中炎症略有减少，以及这些组织中 MT1 表达的差异，可能揭示 MTs 在这些小鼠中具有组织或细胞特异性作用。
