Mitochondrial Metabolism-Mediated Regulation of Adult Neurogenesis

Abstract

The life-long generation of new neurons from radial glia-like neural stem cells (NSCs) is achieved through a stereotypic developmental sequence that requires precise regulatory mechanisms to prevent exhaustion or uncontrolled growth of the stem cell pool. Cellular metabolism is the new kid on the block of adult neurogenesis research and the identity of stage-specific metabolic programs and their impact on neurogenesis turns out to be an emerging research topic in the field. Mitochondrial metabolism is best known for energy production but it contains a great deal more. Mitochondria are key players in a variety of cellular processes including ATP synthesis through functional coupling of the electron transport chain and oxidative phosphorylation, recycling of hydrogen carriers, biosynthesis of cellular building blocks, and generation of reactive oxygen species that can modulate signaling pathways in a redox-dependent fashion. In this review, I will discuss recent findings describing stage-specific modulations of mitochondrial metabolism within the adult NSC lineage, emphasizing its importance for NSC self-renewal, proliferation of neural stem and progenitor cells (NSPCs), cell fate decisions, and differentiation and maturation of newborn neurons. I will furthermore summarize the important role of mitochondrial dysfunction in tissue regeneration and ageing, suggesting it as a potential therapeutic target for regenerative medicine practice.

Keywords: NAD+/NADH; Neurogenesis; adenosin triphosphate (ATP); ageing; electron transport chain (ETC); mitochondrial metabolism; neural stem cells (NSCs); oxidative phosphorylation (oxPhos); reactive oxygen species (ROS); redox state.

Fig.1

Mitochondrial metabolism. Shown is a schematic drawing of the major mitochondrial metabolism pathways discussed in this review (for β-oxidation please refer to Knobloch, 2017 in this issue). For details, please refer to Box 1. Pyruvate is transported from the cytosol to the mitochondrion and enters the Krebs or tricarboxylic (TCA) cycle. TCA and malate/aspartate shuttle serve to recycle hydrogen carriers required for electron transport in the inner mitochondrial membrane (complex I - IV) to generate an electrochemical potential, which provides energy for ATP synthesis by oxidative phosphorylation (complex V). Reactive oxygen species (ROS) are produced by complex I and III of the electron transport chain.

Fig.2

Mitochondrial metabolism-mediated regulation of adult neurogenesis. Schematic drawing summarizing how mitochondrial metabolism influences the distinct developmental steps of adult neurogenesis: neural stem cells (NSCs) generate actively proliferating intermediate progenitor cells (IPCs). IPCs give rise to neuronally committed neuroblasts (NBs) that differentiated into mature neurons. NSCs also generate new astrocytes. Impact of mitochondrial functions on NSC self-renewal, NSCs and IPCs proliferation, differentiation and maturation of progeny is illustrated.