Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis.
Neuron. 2017 Feb 8;93(3):560-573.e6. doi: 10.1016/j.neuron.2016.12.017. Epub 2017 Jan 19.
Beckervordersandforth R1, Ebert B2, Schäffner I3, Moss J4, Fiebig C3, Shin J5, Moore DL6, Ghosh L6, Trinchero MF7, Stockburger C8, Friedland K8, Steib K9, von Wittgenstein J3, Keiner S10, Redecker C10, Hölter SM9, Xiang W3, Wurst W9, Jagasia R11, Schinder AF7, Ming GL5, Toni N4, Jessberger S6, Song H5, Lie DC12.
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.