Mitochondrial Dynamics in the Regulation of Adult Neurogenesis

Abstract

Long-term maintenance of adult neural stem cells (NSCs) is an intricate process of activation, expansion, and differentiation while preserving the stem cell pool. Several regulatory mechanisms underlie the delicate balance in the choice between quiescence versus activation for lifelong NSC maintenance and continuous neurogenesis. Perturbations in this dynamic process result in disease manifestation. The quiescence/activation of NSC was shown to be regulated by the Rb/E2F axis through a molecular program mediated by REST (RE1 Silencing Transcription Factor). Loss of Rb family increased NSC activation at the expense of quiescence through activator E2F transcription factors. The activation and neurogenesis of NSCs were impaired by the loss of effector E2Fs, as well as loss of Opa1, the latter indicating that mitochondrial dynamics is important to maintain stem cell state. Single-cell transcriptome analysis from NSC lineages isolated from adult mouse hippocampus revealed that stem cell progenies are uniquely affected in Opa1-KO leading to impairments in NSC activation and differentiation. Unbiased transcriptional profiling suggested a mitochondrial dysfunction in Opa1-KO that results in activation of classic cellular stress response pathway genes (Atf4, Slc7a11 and Chac1). Thus, the regulatory gene network comprising quiescence (Rb) and activation (E2Fs) programs, and mitochondrial metabolism (Opa1) and their interplay ensures the maintenance of the molecular program of NSC, particularly revealing how it enables stem cells survive stress.