Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network

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.

Proteomic and Metabolomic Analyses of Vanishing White Matter Mouse Astrocytes Reveal Deregulation of ER Functions

“…We looked at general energy consumption by measuring the uptake and secretion of metabolites from the culture medium ( Figure 7A ). As expected, both cultures had taken up glutamate ( Martin-Jimenez et al, 2017 ) and aspartate (which use the same transporters) ( Bender et al, 1997 ), reflecting specific astrocyte function. The uptake of glutamate and aspartate did not influence their intracellular levels (Supplementary File 2 ).…”

“…To investigate other functional changes, we compared the metabolomes of wt and 2b5 ho cells. We detected glutamate uptake in both cultures, which is a typical function of astrocytes, ( Martin-Jimenez et al, 2017 ). This observation further confirms the astrocytic identity of the cultured cells.…”

“…Also, both wt and 2b5 ho cultures showed uptake of pyruvate. Astrocytes convert pyruvate into lactate and glutamate/aspartate into glutamine, cis -aconitate and α-ketoglutarate ( Martin-Jimenez et al, 2017 ). Indeed, the wt as well as the 2b5 ho cultures secreted lactate, glutamine, cis -aconitate and α-ketoglutarate ( Figure 7A ).…”

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

“…We tested our models for 16 metabolic tasks (Supplementary file 11) that are brain specific and the models passed 50-70% of those tests, except for superior temporal gyrus metabolic network. As astrocytes are predominantly involved in maintaining brain physiology 64 , we used objective function of astrocytes for our brain metabolic networks. We constrained bounds of exchange reactions using information from a published work on metabolic interactions between cell types in brain 65 .…”

Advances in Astrocyte Computational Models: From Metabolic Reconstructions to Multi-omic Approaches

“…The metabolic pathways modulated by astrocytes have been studied both experimentally and through the use of different computational models (Yu et al, 2002 ; Jin and Brennan, 2008 ; Sertbaş et al, 2014 ; Martín-Jiménez et al, 2017 ). However, there is still a lack of understanding of the metabolic relationship between these interactions and drug response, environmental agents, or pathological conditions.…”