Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis.

Ryann M Fame,Maria K Lehtinen

doi:10.3389/fcell.2021.780207

Ryann M Fame, Maria K Lehtinen

Open Access

https://doi.org/10.3389/fcell.2021.780207

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Abstract

Function of the mature central nervous system (CNS) requires a substantial proportion of the body’s energy consumption. During development, the CNS anlage must maintain its structure and perform stage-specific functions as it proceeds through discrete developmental stages. While key extrinsic signals and internal transcriptional controls over these processes are well appreciated, metabolic and mitochondrial states are also critical to appropriate forebrain development. Specifically, metabolic state, mitochondrial function, and mitochondrial dynamics/localization play critical roles in neurulation and CNS progenitor specification, progenitor proliferation and survival, neurogenesis, neural migration, and neurite outgrowth and synaptogenesis. With the goal of integrating neurodevelopmental biologists and mitochondrial specialists, this review synthesizes data from disparate models and processes to compile and highlight key roles of mitochondria in the early development of the CNS with specific focus on forebrain development and corticogenesis.

Highlights

Mitochondrial dysfunction underlies most inherited metabolic disorders
Further implicating glucose metabolism in this developmental decision point between stem cell and neurogenesis, metformin, an FDA approved compound for the treatment of diabetes that acts through transient inhibition of mitochondrial ETC complex 1 (Viollet et al, 2012), has been shown to enhance neuronal differentiation through activating the AMPK pathway in adult neural stem cells (Fatt et al, 2015), suggesting similar effects in corticogenesis as well
Downstream signaling of NAD+/NADH oxidative stress occurs through sirtuin (Sirt1) activation of H4K15 acetylation, and that direct activation of Sirt1 can negate the effects of chemically inhibiting fission in these progenitors (Iwata et al, 2020), indicating a deep relationship between reactive oxygen species (ROS), sirtuins, mitochondrial dynamics, and cortical neurogenesis

Summary

Introduction

Mitochondrial dysfunction underlies most inherited metabolic disorders. The estimated prevalence for mitochondrial diseases is 1:5,000 (Schaefer et al, 2004). Detailed examination of forebrain progenitors during neurulation reveals changes in mitochondrial morphology, gene expression, and activity suggesting a metabolic transition in forebrain precursor cells from glycolysis at E8.5 in mice to oxidative phosphorylation at E10.5 (Fame et al, 2019).

Results

Conclusion