RT Journal Article
SR Electronic
T1 Metabolic switch in the aging astrocyte evidenced via integrative approach comprising network and transcriptome analyses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.31.478210
DO 10.1101/2022.01.31.478210
A1 Alejandro Acevedo
A1 Felipe Torres
A1 Miguel Kiwi
A1 Felipe Baeza-Lehnert
A1 L. Felipe Barros
A1 Dasfne Lee-Liu
A1 Christian González-Billault
YR 2022
UL http://biorxiv.org/content/early/2022/02/02/2022.01.31.478210.abstract
AB Central energy metabolism is a pivotal process dysregulated during brain aging. The neuron and the astrocyte form an extensive interconnected metabolic network that allows achieving the high energy demand required by the neuron to propagate information in the brain. While most of this energy is utilized to re-establish cation gradients in neurons and glial cells, which specific genes in the neuron-astrocyte metabolic network are essential for continuous neurotransmission and are responsible for cognitive decline during brain aging remains largely unknown.To identify these gene products, we used a novel approach to analyze the neuron-astrocyte metabolic network, integrating network flux (optimality) and structure (centrality) and determined how the contribution of each gene in the network affected its function. Genes with the highest optimality and centrality scores were termed “hub genes.” They were searched in astrocyte and neuron transcriptomic databases to identify “differential hub genes,” which were differentially expressed during neurotransmission or aging.The identified differential hub genes suggest that during brain aging: 1) The neuron suffers energetic deficit by substantial downregulation of Krebs cycle genes including mdh1 and mdh2 (malate-aspartate shuttle), while the astrocyte undergoes a metabolic switch from aerobic glycolysis to oxidative phosphorylation, hampering the supply of lactate to the neuron; 2) Branched-chain amino acid (BCAA) degradation hub genes were downregulated, including hub gene dld, an integrative gene that encodes for a subunit in BCAA-, pyruvate- and ⍰- ketoglutarate dehydrogenase complexes; and 3) Increased ketone body synthesis in the neuron and augmented astrocytic utilization, in line with neuronal energy deficit in favor of astrocytes.Differential hub gene identification was robust and resulted in novel candidates for future pre-clinical studies targeting energy metabolism to prevent age-associated cognitive decline. Importantly, our approach narrows down the number of candidate genes identified in transcriptomic databases by two orders of magnitude. This method may be applied to other metabolic cellular models in future omics studies.Competing Interest StatementThe authors have declared no competing interest.