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The Novel Neurogenic NeuroD6-Mitochondria Axis: Implications for Neuronal Differentiation and Survival Open Access

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Mitochondria play a vital role during neurogenesis by providing energy in the form of ATP to fuel many processes, including cytoskeletal remodeling, plasmalemmal biogenesis, axonal and dendritic outgrowth, growth cone physiology, and synaptic activity. A growing body of evidence has highlighted mitochondrial dysfunction as a common theme in numerous neurodevelopmental disorders. Yet, little is known about the intrinsic neurogenic regulation of mitochondrial biogenesis and bioenergetics and how the mitochondrial biomass and functions are coupled to the distinct stages of neuronal differentiation to meet the unique energy demands of developing neurons. The basic Helix-Loop-Helix (bHLH) differentiation factors belonging to the NeuroD family are excellent candidates to regulate the tight coupling between neuronal differentiation and energy metabolism, as they play an active role in initiating and executing terminal differentiation during neurogenesis. More specifically, NeuroD6 could effectively coordinate and regulate the constant interplay between neuritogenesis and energy generation, as it possesses differentiation and survival properties combined with its abilities to trigger a comprehensive network of mitochondrial-related genes. The primary objective of this research project was to test this hypothesis in the context of neuronal differentiation and survival. Our collective results demonstrate that the neurogenic transcription factor NeuroD6 acts as a co-regulator of neuronal differentiation and energy metabolism. NeuroD6 plays an integrative role in coordinating increase in mitochondrial mass with cytoskeletal remodeling during the early stages of neuronal differentiation, thereby facilitating proper trafficking of mitochondria to regions of intense energy demand, such as branching points and the growth cone. Moreover, NeuroD6 has the ability to stimulate mitochondrial bioenergetic functions by simultaneously increasing the mitochondrial membrane potential and levels of ATP production, thereby generating an energetic reserve. Consequently, NeuroD6 endows the neuronal PC12-ND6 cells with neuroprotective properties upon oxidative stress and exposure to mitochondrial stressors by inducing an adaptive bioenergetic response involving maintenance of the mitochondrial biomass, mitochondrial membrane potential and ATP levels, in conjunction with preservation of the cytoskeletal network. Thus, having concurrent regulation of mitochondrial homeostasis and neuronal differentiation and survival by the same transcription factor substantially improves the efficiency of this regulatory process. In conclusion, further elucidation of the NeuroD6-mediated transcriptional regulation of mitochondrial biogenesis and function during neurogenesis may offer insights into possible therapeutic implications for neurodevelopmental disorders with a mitochondrial etiology.

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