Mitochondrial Complex I Function Is Essential for Neural Stem/Progenitor Cells Proliferation and Differentiation.

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.