Cabello-Rivera Daniel, Sarmiento-Soto Helia, López-Barneo José, Muñoz-Cabello Ana M
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
Facultad de Medicina, Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain.
Front Neurosci. 2019 Jun 26;13:664. doi: 10.3389/fnins.2019.00664. eCollection 2019.
Neurogenesis in developing and adult mammalian brain is a tightly regulated process that relies on neural stem cell (NSC) activity. There is increasing evidence that mitochondrial metabolism affects NSC homeostasis and differentiation but the precise role of mitochondrial function in the neurogenic process requires further investigation. Here, we have analyzed how mitochondrial complex I (MCI) dysfunction affects NSC viability, proliferation and differentiation, as well as survival of the neural progeny. We have generated a conditional knockout model (hGFAP-NDUFS2 mice) in which expression of the NDUFS2 protein, essential for MCI function, is suppressed in cells expressing the Cre recombinase under the human glial fibrillary acidic protein promoter, active in mouse radial glial cells (RGCs) and in neural stem cells (NSCs) that reside in adult neurogenic niches. In this model we observed that survival of central NSC population does not appear to be severely affected by MCI dysfunction. However, perinatal brain development was markedly inhibited and knockout mice died before the tenth postnatal day. In addition, studies of subventricular zone NSCs showed that active neural progenitors require a functional MCI to produce ATP and to proliferate. differentiation of neural precursors into neurons and oligodendrocytes was also profoundly affected. These data indicate the need of a correct MCI function and oxidative phosphorylation for glia-like NSC proliferation, differentiation and subsequent oligodendrocyte or neuronal maturation.
在发育中和成年哺乳动物大脑中，神经发生是一个受到严格调控的过程，依赖于神经干细胞（NSC）的活性。越来越多的证据表明，线粒体代谢会影响神经干细胞的稳态和分化，但线粒体功能在神经发生过程中的确切作用仍需进一步研究。在这里，我们分析了线粒体复合体I（MCI）功能障碍如何影响神经干细胞的活力、增殖和分化，以及神经后代的存活。我们构建了一个条件性敲除模型（hGFAP-NDUFS2小鼠），在该模型中，在人胶质纤维酸性蛋白启动子控制下表达Cre重组酶的细胞中，MCI功能所必需的NDUFS2蛋白的表达被抑制，该启动子在小鼠放射状胶质细胞（RGC）和位于成年神经发生微环境中的神经干细胞（NSC）中具有活性。在这个模型中，我们观察到中枢神经干细胞群体的存活似乎没有受到MCI功能障碍的严重影响。然而，围产期脑发育明显受到抑制，敲除小鼠在出生后第10天之前死亡。此外，对脑室下区神经干细胞的研究表明，活跃的神经祖细胞需要功能性的MCI来产生ATP并进行增殖。神经前体细胞向神经元和少突胶质细胞的分化也受到了深刻影响。这些数据表明，胶质样神经干细胞的增殖、分化以及随后的少突胶质细胞或神经元成熟需要正确的MCI功能和氧化磷酸化。
