eIF2B Mutations Cause Mitochondrial Malfunction in Oligodendrocytes.

Neuromolecular medicine (2019-05-28)
Melisa Herrero, Shir Mandelboum, Orna Elroy-Stein

Vanishing white matter (VWM) disease (OMIM#306896) is an autosomal recessive neurodegenerative leukodystrophy caused by hypomorphic mutations in any of the five genes encoding the subunits of eukaryotic translation initiation factor 2B (eIF2B). The disease is manifested by loss of cerebral white matter and progressive deterioration upon exposure to environmental and physiological stressors. "Foamy" oligodendrocytes (OLG), increased numbers of oligodendrocytes precursor cells (OPC), and immature defective astrocytes are major neuropathological denominators. Our recent work using Eif2b5R132H/R132H mice uncovered a fundamental link between eIF2B and mitochondrial function. A decrease in oxidative phosphorylation capacity was observed in mutant astrocytes and fibroblasts. While an adaptive increase in mitochondria abundance corrects the phenotype of mutant fibroblasts, it is not sufficient to compensate for the high-energy demand of astrocytes, explaining their involvement in the disease. To date, astrocytes are marked as central for the disease while eIF2B-mutant OLG are currently assumed to lack a cellular phenotype on their own. Here we show a reduced capacity of eIF2B-mutant OPC isolated from Eif2b5R132H/R132H mice to conduct oxidative respiration despite the adaptive increase in their mitochondrial abundance. We also show their impaired ability to efficiently complete critical differentiation steps towards mature OLG. The concept that defective differentiation of eIF2B-mutant OPC could be a consequence of mitochondrial malfunction is in agreement with numerous studies indicating high dependency of differentiating OLG on accurate mitochondrial performance and ATP availability.

Product Number
Product Description

Insulin from bovine pancreas, powder, BioReagent, suitable for cell culture
Antimycin A from Streptomyces sp.
Rotenone, ≥95%
Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, ≥98% (TLC), powder
3,3′,5-Triiodo-L-thyronine sodium salt, powder, BioReagent, suitable for cell culture
Poly-D-lysine hydrobromide, mol wt 70,000-150,000
apo-Transferrin human, powder, BioReagent, suitable for cell culture, ≥98% (agarose gel electrophoresis)
Oligomycin from Streptomyces diastatochromogenes, ≥90% total oligomycins basis (HPLC)
Progesterone, powder, BioReagent, suitable for cell culture
Putrescine dihydrochloride, powder, BioReagent, suitable for cell culture
N-Acetyl-L-cysteine, BioXtra, ≥99% (TLC)
Bovine Serum Albumin, lyophilized powder, essentially globulin free, BioReagent, suitable for cell culture
Anti-Galactocerebroside antibody produced in rabbit, whole antiserum

Social Media

LinkedIn icon
Twitter icon
Facebook Icon
Instagram Icon


Research. Development. Production.

We are a leading supplier to the global Life Science industry with solutions and services for research, biotechnology development and production, and pharmaceutical drug therapy development and production.

© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

Reproduction of any materials from the site is strictly forbidden without permission.