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

Daniel Cabello-Rivera,José López-Barneo,Helia Sarmiento-Soto,Ana M Muñoz-Cabello

doi:10.3389/fnins.2019.00664

Abstract

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 Ndufs2 knockout mice died before the tenth postnatal day. In addition, in vitro studies of subventricular zone NSCs showed that active neural progenitors require a functional MCI to produce ATP and to proliferate. In vitro 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.

Highlights

Generation of neurons and glial cells in the developing central nervous system (CNS) are tightly regulated processes that rely on the activity of neural stem and progenitor cells as well as on extracellular signals provided by the surrounding niche (Taverna et al, 2014; Bond et al, 2015)
At postnatal day (P) 0 human glial fibrillary acidic protein (hGFAP)-NDUFS2 mice were apparently indistinguishable from littermates and their brains were macroscopically similar to controls (Figure 1A), the histological analyses revealed a decrease in cortical thickness (Figure 1B) and subtle hippocampal abnormalities (Figure 1C)
We observed a marked reduction in the brain size of hGFAP-NDUFS2 mice, in which recombination efficiency was assessed (Figure 2). hGFAPNDUFS2 brains showed profound anatomical abnormalities that were more evident in dorsal cortical areas, the hippocampus and cerebellum (Figures 2B–F)

Summary

Introduction

Generation of neurons (neurogenesis) and glial cells (gliogenesis) in the developing central nervous system (CNS) are tightly regulated processes that rely on the activity of neural stem and progenitor cells as well as on extracellular signals provided by the surrounding niche (Taverna et al, 2014; Bond et al, 2015). There is increasing evidence supporting the hypothesis that mitochondrial function is essential for post-mitotic neuron survival, and for other aspects of neural stem and progenitor cells homeostasis, affecting survival and proliferation of these cell populations (Díaz-Castro et al, 2015; Beckervordersandforth et al, 2017; Khacho et al, 2017; Khacho and Slack, 2018)

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Conclusion