Metabolism navigates neural cell fate in development, aging and neurodegeneration.

Larissa Traxler,Davide Stefanoni,Jerome Mertens,Angelo D'Alessandro,Jessica Lagerwall,Sophie Eichhorner

doi:10.1242/dmm.048993

Larissa Traxler, Davide Stefanoni + Show 4 more

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https://doi.org/10.1242/dmm.048993

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Abstract

ABSTRACTAn uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is supported by genetic defects in the oxidative phosphorylation mechanism often contributing towards neurodevelopmental disorders and changes in glucose metabolism presenting as a hallmark feature in age-dependent neurodegenerative disorders. However, as recent studies have illuminated roles of cellular metabolism that span far beyond mere energetics, it would be valuable to first comprehend the physiological involvement of metabolic pathways in neural cell fate and function, and to subsequently reconstruct their impact on diseases of the brain. In this Review, we first discuss recent evidence that implies metabolism as a master regulator of cell identity during neural development. Additionally, we examine the cell type-dependent metabolic states present in the adult brain. As metabolic states have been studied extensively as crucial regulators of malignant transformation in cancer, we reveal how knowledge gained from the field of cancer has aided our understanding in how metabolism likewise controls neural fate determination and stability by directly wiring into the cellular epigenetic landscape. We further summarize research pertaining to the interplay between metabolic alterations and neurodevelopmental and psychiatric disorders, and expose how an improved understanding of metabolic cell fate control might assist in the development of new concepts to combat age-dependent neurodegenerative diseases, particularly Alzheimer's disease.

Highlights

Cell identity and function are inseparable from a cell’s metabolism of energy and molecular components
Evidence indicates that glial cells, and neurons, can enter a senescence-like state, and that senescent dopaminergic neurons accumulate during aging and might contribute to Parkinson’s disease (PD) progression via dysfunction and the senescence-associated secretory phenotype (SASP) (Box 2) (Martínez-Cué and Rueda, 2020; Riessland et al, 2019; Saez-Atienzar and Masliah, 2020)
Changes in metabolic genes can cause late-onset neurodegeneration, and age- and disease-related metabolic state switches put neural cell-type identity under siege, which leads to a loss of resilience of neural cells and their eventual degeneration

Summary

Introduction

Cell identity and function are inseparable from a cell’s metabolism of energy and molecular components. A Warburg-like metabolic switch in brain cells, including neurons, may further cause neural cell de-differentiation and loss of cell fate stability, leading to loss of functionality (synaptic transmission) and, cell death (Mertens et al, 2021).

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Conclusion