EIF2B links translational control to mitochondrial oxidative phosphorylation in Vanishing White Matter disease

ABSTRACT: Eukaryotic translation initiation factor 2B is a master regulator of protein synthesis under normal and stress conditions. Mutations in any of the five genes encoding its subunits lead to Vanishing White Matter (VWM) disease, a recessive genetic deadly illness caused by progressive loss of white matter in the brain. Although fibroblasts are not involved in the disease, we used mouse embryo fibroblasts (MEFs) isolated from Eif2b5R132H/R132H mice to demonstrate their compromised mitochondrial translation, unbalanced stoichiometry of proteins involved in oxidative phosphorylation, decreased basal and maximal oxygen consumption rate, and increased mitochondrial abundance reflecting adaptation to meet energy requirements. The involvement of eIF2B in mitochondrial function and abundance was validated in primary astrocytes isolated from Eif2b5R132H/R132H mice brains. We found that oxidative respiration deficiency is more robust in astrocytes and does not reach normal cellular levels even following 2-fols increase in mitochondrial content. The consequent increase in basal and maximal glycolysis in mutant astrocytes demonstrates their enhanced sensitivity to the impaired oxidative phosphorylation, illuminating the importance of mitochondrial function in VWM pathology. The data demonstrates the critical role of eIF2B in tight coordination of expression from nuclear and mitochondrial genomes. Further dissection of the signalling network associated with eIF2B function will help generating therapeutic strategies for VWM disease and possibly other neurodegenerative disorders.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Fibroblast

SUBMITTER: Tamar Geiger  

LAB HEAD: Tamar Geiger

PROVIDER: PXD005854 | Pride | 2017-07-11

REPOSITORIES: Pride