Studies revealing molecular mechanisms underlying neural specification have majorly focused on the role played by different transcription factors, but less on non-nuclear components. Earlier, we reported mitochondrial superoxide dismutase (SOD2) to be essential for self-renewal and pluripotency of mouse embryonic stem cells (mESCs). In the present study, we found SOD2 to be specifically required for neural lineage, but not the meso- or endoderm specification. Temporally, SOD2 regulated early neural genes, but not the matured genes, by modulating mitochondrial dynamics—specifically by enhancing the mitochondrial fusion protein Mitofusin 2 (MFN2). Bio-complementation strategy further confirmed SOD2 to enhance mitochondrial fusion process independent of its antioxidant activity. Over-expression of SOD2 along with OCT4, but neither alone, transdifferentiated mouse fibroblasts to neural progenitor-like colonies, conclusively proving the neurogenic potential of SOD2. In conclusion, our findings accredit a novel role for SOD2 in early neural lineage specification.

揭示神经规范基础的分子机制的研究主要集中在不同转录因子发挥的作用上，而较少关注非核成分。先前，我们报道线粒体超氧化物歧化酶（SOD2）对于小鼠胚胎干细胞（mESCs）的自我更新和多能性至关重要。在本研究中，我们发现SOD2是神经谱系特别需要的，但不是中胚层或内胚层规范的。暂时，SOD2通过调节线粒体动力学来调节早期的神经基因，而不调节成熟的基因，特别是通过增强线粒体融合蛋白线粒体融合蛋白2（MFN2）。生物补充策略进一步证实了SOD2增强线粒体融合过程，而与其抗氧化活性无关。SOD2和OCT4一起过表达，但没有一个单独出现，将小鼠成纤维细胞转分化为神经祖细胞样菌落，最终证明了SOD2的神经源性潜力。总之，我们的发现证实了SOD2在早期神经谱系规范中的新作用。