Mitochondria Modify Exercise-Induced Development of Stem Cell-Derived Neurons in the Adult Brain

Abstract

Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesisdependent hippocampal plasticity.

Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin

“…Physical exercise has been shown to enhance adiponectin production by reducing fat mass and inflammation in obese/diabetic patients (12). Given the important role of AMPK in mitochondrial biogenesis (45), which is required for running-accelerated newborn neuron maturation (46), increase in hippocampal adiponectin after running may modulate mitochondria biogenesis via activation of AMPK in the newborn cells, thereby enhancing neurogenesis.…”

Metabolic control of adult neural stem cell behavior

“…Whether this holds true for mammalian NSPCs remains to be determined. Further evidence that there is an increase in oxidative phosphorylation with neuronal differentiation comes from a recent study by Steib and colleagues, who have shown that the development of new neurons in adult mice is paralleled by extensive changes in mitochondrial mass, distribution, and shape (Steib et al, 2014). When inhibiting a mitochondrial fission factor necessary for increasing the numbers of mitochondria, maturation and survival of newborn neurons was strongly decreased.…”

Lessons Learned from Transgenic Mouse Models for the Therapeutic Use of Drp1 Inhibitors

“…Further, two Drp1 constitutive knockout mouse models displayed severe neurodevelopmental defects [25,26], and similar observations were made in a human infant born with a de novo dominant-negative Drp1 mutation [27] and in patients with mutations in the mitochondrial Drp1 receptor, Mff [28]. Moreover, deleting Drp1 in adult neuronal stem cells leads to defective differentiation [29,30]. The importance of Drp1 function for differentiating and proliferating tissues is also underlined by the decrease of tumor aggressiveness upon treatment with Drp1 inhibitors [31][32][33].…”