Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network.

Cynthia A Martín-Jiménez,Janneth González,Diego Salazar-Barreto,George E Barreto

doi:10.3389/fnagi.2017.00023

Abstract

Astrocytes are the most abundant cells of the central nervous system; they have a predominant role in maintaining brain metabolism. In this sense, abnormal metabolic states have been found in different neuropathological diseases. Determination of metabolic states of astrocytes is difficult to model using current experimental approaches given the high number of reactions and metabolites present. Thus, genome-scale metabolic networks derived from transcriptomic data can be used as a framework to elucidate how astrocytes modulate human brain metabolic states during normal conditions and in neurodegenerative diseases. We performed a Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network with the purpose of elucidating a significant portion of the metabolic map of the astrocyte. This is the first global high-quality, manually curated metabolic reconstruction network of a human astrocyte. It includes 5,007 metabolites and 5,659 reactions distributed among 8 cell compartments, (extracellular, cytoplasm, mitochondria, endoplasmic reticle, Golgi apparatus, lysosome, peroxisome and nucleus). Using the reconstructed network, the metabolic capabilities of human astrocytes were calculated and compared both in normal and ischemic conditions. We identified reactions activated in these two states, which can be useful for understanding the astrocytic pathways that are affected during brain disease. Additionally, we also showed that the obtained flux distributions in the model, are in accordance with literature-based findings. Up to date, this is the most complete representation of the human astrocyte in terms of inclusion of genes, proteins, reactions and metabolic pathways, being a useful guide for in-silico analysis of several metabolic behaviors of the astrocyte during normal and pathologic states.

Highlights

Astrocytes are the most numerous glial cells found in the vertebrate brain (Verkhratsky et al, 2014)
The present model for astrocyte metabolism can be classified based on the following categories: (A) enzymatic classification (EC-number); (B) gene association; (C) subcellular locations and (D) metabolic pathways
The results presented here were generated from flux distributions adjusted to the metabolic behavior of human astrocytes in response to maximum requirements of associated with reduced energy production (ATP), glutamate capture and later conversion to glutamine

Summary

Introduction

Astrocytes are the most numerous glial cells found in the vertebrate brain (Verkhratsky et al, 2014). These cells have a major role in the functions of the central nervous system and participate in key processes such as neurogenesis (Figueiredo et al, 2014), synaptogenesis (Hughes et al, 2010), neuro-inflammation (van Dijk et al, 2015) and neuro-modulation. The expression of biological phenomena using mathematical models has been used to understand how information, energy and matter behaves in the cell and to get an efficient statistical inference in experimental research by studying the dynamical behavior of cell (Najafi et al, 2014; Vanlier et al, 2014; Özcan and Çakır, 2016; Rajkumar et al, 2016)

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