Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

Abstract

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.

Keywords: adult neurogenesis; autophagy/mitophagy; cognitive dysfunction; hippocampus; mitochondrial dynamics; mitochondrial metabolism; mood disorders; neurodegeneration; psychological stress; reactive oxygen species (ROS).

Figure 1

Simplified depiction of the cellular metabolic pathways discussed in this review. Glycolysis converts glucose into pyruvate that is transported into mitochondria and converted to acetyl-CoA. Acetyl-CoA is also produced during fatty acid oxidation (FAO) in the mitochondrial matrix. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle that produces the substrates NADH and FADH₂ (for respiratory complex I and II, respectively) required for oxidative phosphorylation (OXPHOS). Electron transport during respiration is coupled to proton (H⁺) export from the mitochondrial matrix to the inter-membrane space. This generates an electrochemical gradient Δψm where the H⁺ concentration is higher in the inter-membrane space than in the matrix. When H⁺ flow back into the matrix through ATP synthase (complex V), the energy of this gradient is used to produce ATP. During OXPHOS, electrons leak at respiratory complex I and III and react with molecular oxygen to produce ROS (superoxide, which is converted to H₂O₂). In addition to the TCA cycle, NADH and FADH₂ are produced during FAO. Citrate produced in the TCA cycle exits mitochondria and is converted back to acetyl-CoA in the cytoplasm, where it is used to generate complex fatty acids through de novo lipogenesis. For FAO, complex fatty acids must be transported into the mitochondrial matrix via a carnitine shuttle system and two distinct transporters located in the outer and inner mitochondrial membrane. For simplicity, transporter proteins for various molecules are not shown in the figure. Arrows with dashes indicate the direction of proton (H⁺) transport/flow between the mitochondrial matrix and the intermembrane space.

Figure 2

Simplified scheme of autophagy and mitophagy pathways. (A) Basal macro-autophagy (autophagy) degrades and recycles cellular contents at steady state. The activity of autophagy is regulated by nutrient (e.g., glucose) and energy (AMP/ATP ratio) availability through PI3K/Akt signaling, mTORC1, and AMPK. Autophagy is induced under conditions of nutrient and energy starvation and by oxidative stress, i.e., conditions that require enhanced recycling of cellular materials to sustain cell metabolism and degradation of oxidized and aggregated proteins to protect cells against stress-induced damage. At the start of autophagy, a double membrane (isolation membrane or phagophore) forms and expands around the cellular material to engulf the material within an autophagosome. The autophagosome fuses with a lysosome that contains hydrolases necessary to degrade the contents within the resulting autolysosome. For details, including stage-specific autophagy regulators, please refer to [96]. (B) Mitophagy is a subclass of autophagy that selectively degrades depolarized and damaged mitochondria. There are two mitophagy mechanisms (for details, see [55,68]). In PINK1/Parkin-dependent mitophagy, PINK1 selectively accumulates on depolarized mitochondria (due to import deficiency), and PINK1 and Parkin cooperate to poly-ubiquitinate specific proteins at the surface of depolarized mitochondria. PINK1-phosphorylated polyubiquitin serves a signal for autophagy adapters (p62, OPTN, NDP52) to bind to the damaged mitochondria and target them to autophagosomes via interaction with LC3 of the isolation membrane. In receptor-mediated mitophagy, mitophagy receptors (BNIP3, NIX, FUNDC1) localize to the mitochondrial membrane and directly interact with LC3.

Figure 3

Stage-specific metabolic pathways, mitochondrial dynamics, and ROS regulate cell transition and progression during adult neurogenesis. Neural stem cells (NSC) rely on glycolysis and fatty acid oxidation (FAO) for stemness and self-renewal. An increase of mitochondrial oxidative phosphorylation (OXPHOS) at the expense of FAO and upregulation of de novo lipogenesis in the cytoplasm promote proliferation of NSC and progression toward intermediate progenitor cells (IPC). As IPC begin to differentiate to neuroblasts and further progress to become mature newborn neurons, OXPHOS is crucial to supply the growing cells with sufficient energy. In this phase, mitochondrial biogenesis, fission, and transport are essential to increase mitochondrial content and distribute newly generated mitochondria into the growing and distal branches of maturing dendrites. However, because fragmented mitochondria produce less ATP and fission increases ROS, fission must be transient and followed by fusion. Overall, the mitochondrial morphology changes from fragmented to increasingly elongated during neurogenesis consistent with the progressive reliance of cells on OXPHOS. Reactive oxygen species (ROS) generated by several different NADPH oxidases (Nox proteins) regulate the transition between qNSC and aNSC, NSC renewal, and NSPC proliferation, which has been reviewed elsewhere [79]. In addition, ROS/Nrf2-dependent signaling triggered by mitochondrial fission promotes the transition from aNSC to differentiation-committed IPC. However, the exact role of ROS in this step remains somewhat ambiguous. For more details, please refer to the main text.