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.