How do eIF2B-mutant astrocytes adapt to energy stress?

VWM disease is a recessive genetic neurodegenerative pathology, caused by mutations in any of the five genes encoding the subunits of eIF2B, a translation initiation factor. Using the Eif2b5^R132H/R132H (Mut) mouse model we provided evidence that the mutations in eIF2B cause lack of tight coordination between the cytosolic and mitochondrial translation machineries, resulting in impaired oxidative phosphorylation.

The need of astrocytes to synthesize and secrete large number of proteins in a short time frame and their challenging energy metabolism to support brain homeostasis, explain why translation impairments and lack of available energy take their toll on astrocytes and render them extremely sensitive to eIF2B mutations.

Glucose is the main fuel used to satisfy astrocytes energy requirements. We recently found that glucose starvation of primary astrocytes isolated from Mut and WT mice brains, leads to increase in oxidative respiration due to a switch of the metabolic fuel from glucose to fatty acids. However, an increase in replication of mitochondrial DNA accompanies this strategy only in Mut astrocytes. The higher levels of mitochondrial DNA in mutants increases the level of electron transfer chain (ETC) complexes and improves oxidative phosphorylation efficiency. Interestingly, despite the strategic efforts of Mut astrocytes, they cannot reach WT ATP levels under conditions of glucose starvation. Our data reflects the increased sensitivity of Eif2b-Mut astrocytes to glucose concentrations in the brain, further supporting their role in the neurodegeneration phenotype of VWMD patients.