Abstract
Translation initiation factor 2B (eIF2B) is a master regulator of global protein synthesis in all cell types. The mild genetic Eif2b5(R132H) mutation causes a slight reduction in eIF2B enzymatic activity which leads to abnormal composition of mitochondrial electron transfer chain complexes and impaired oxidative phosphorylation. Previous work using primary fibroblasts isolated from Eif2b5(R132H/R132H) mice revealed that owing to increased mitochondrial biogenesis they exhibit normal cellular ATP level. In contrast to fibroblasts, here we show that primary astrocytes isolated from Eif2b5(R132H/R132H) mice are unable to compensate for their metabolic impairment and exhibit chronic state of low ATP level regardless of extensive adaptation efforts. Mutant astrocytes are hypersensitive to oxidative stress and to further energy stress. Moreover, they show migration deficit upon exposure to glucose starvation. The mutation in Eif2b5 prompts reactive oxygen species (ROS)-mediated inferior ability to stimulate the AMP-activated protein kinase (AMPK) axis, due to a requirement to increase the mammalian target of rapamycin complex-1 (mTORC1) signalling in order to enable oxidative glycolysis and generation of specific subclass of ROS-regulating proteins, similar to cancer cells. The data disclose the robust impact of eIF2B on metabolic and redox homeostasis programs in astrocytes and point at their hyper-sensitivity to mutated eIF2B. Thereby, it illuminates the central involvement of astrocytes in Vanishing White Matter Disease (VWMD), a genetic neurodegenerative leukodystrophy caused by homozygous hypomorphic mutations in genes encoding any of the 5 subunits of eIF2B.
Highlights
Translation initiation factor 2B, a master regulator of protein synthesis under normal and stress conditions, is a decameric complex composed of two homo-pentamers of eIF2B1-5 subunits which are evolutionary conserved from yeast to mammals [1,2]
We found that Mut astrocytes exhibit 21%, 36% and 45% lower oxidation efficiency of each of these fuels, respectively, compared to WT (Figure 1A)
These findings show that AMPK activity is paradoxically lower in primary astrocytes and whole brain tissues expressing mutated eIF2B, despite their poor energetic status
Summary
Translation initiation factor 2B (eIF2B), a master regulator of protein synthesis under normal and stress conditions, is a decameric complex composed of two homo-pentamers of eIF2B1-5 subunits which are evolutionary conserved from yeast to mammals [1,2]. EIF2B is inhibited via phosphorylation by glycogen synthase kinase 3 (GSK3) [8] Another important inhibitory mechanism under various stress conditions is mediated by phosphorylation of the alpha subunit of eIF2 by one of four different kinases (heme-regulated inhibitor, HRI; general control non-derepressible-2, GCN2; protein kinase R, PKR; and PKR-like endoplasmic reticulum kinase, PERK) which turns it into a competitive inhibitor of eIF2B. The latter marks the beginning of an expression program termed integrated stress response (ISR) which includes feedback dephosphorylation of eIF2α [9]
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