Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis

Abstract

SUMMARY Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Several other hallmarks of aging may contribute to impaired neurogenesis during aging. Aging neural progenitor cells exhibit reduced mitochondrial oxidative metabolism (Stoll et al, 2011), and genetic compromise of mitochondrial ETC function in hippocampal neuronal progenitor cells in adult mice impairs neurogenesis in a manner similar to that seen in normal aging (Beckervordersandforth et al, 2017). Oxidative stress, impaired DNA repair, and inflammation may also contribute to age-related reductions in neurogenesis (Ekdahl et al, 2003; Kim et al, 2008; Regnell et al, 2012; L’Episcopo et al, 2013).…”

Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain

“…Within the adult brain, NSCs have the capacity to expand and generate new neurons throughout life (Gage, 2000;Cameron and McKay, 2001;Duan et al, 2008). Although the importance of mitochondrial function during differentiation has been well established within the hematopoetic, mesenchymal, and cardiac systems (Piccoli et al, 2005;Chung et al, 2007;Chen et al, 2008), to name a few, only recently have studies emerged showing this to also be true in the case of neuronal differentiation (Knobloch et al, 2013;Khacho et al, 2016;Beckervordersandforth et al, 2017b;Knobloch and Jessberger, 2017).…”

“…The differentiation of stem cells to a specific lineage is accompanied by a metabolic switch and activation of mitochondrial respiration resulting in the shift from glycolysis to OXPHOS as the predominant energy source (Mandal et al, 2011;Shyh-Chang et al, 2013;Takubo et al, 2013). Similarly, in vivo, in vitro, and single-cell transcriptomic studies have established that a metabolic shift also occurs during neurogenesis, whereby NSCs display a glycolytic metabolism while postmitotic neurons are heavily reliant an OXPHOS (Llorens-Bobadilla et al, 2015;Shin et al, 2015;Agostini et al, 2016;Khacho et al, 2016;Beckervordersandforth et al, 2017b). The metabolic switch during neuronal differentiation is mediated through coordinated modification in the expression of metabolic regulators.…”

“…Over time, the sustained dysfunction of mitochondria resulted in the eventual depletion of the adult NSC pool and loss of adult neurogenesis (Khacho et al, 2017). Likewise, disruption of mitochondrial function, when restricted solely to the adult NSC population, was shown to cause impairment in adult neurogenesis (Beckervordersandforth et al, 2017a). In this case, mitochondrial dysfunction, which was induced by loss of the mitochondrial transcription factor TFAM, resulted in the inability of activated NPCs to undergo proper differentiation into neurons (Beckervordersandforth et al, 2017a).…”

“…Likewise, disruption of mitochondrial function, when restricted solely to the adult NSC population, was shown to cause impairment in adult neurogenesis (Beckervordersandforth et al, 2017a). In this case, mitochondrial dysfunction, which was induced by loss of the mitochondrial transcription factor TFAM, resulted in the inability of activated NPCs to undergo proper differentiation into neurons (Beckervordersandforth et al, 2017a). Although acute loss of mitochondrial dysfunction did not cause a defect in adult NSCs in this study, it would be interesting to examine adult NSC function following longer periods of time.…”