{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:06:58Z","timestamp":1791295618625,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,4,16]],"date-time":"2017-04-16T00:00:00Z","timestamp":1492300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The Legacy Heritage Bio-Medical Program of the Israel Science Foundation","award":["1629\/13"],"award-info":[{"award-number":["1629\/13"]}]},{"name":"Israel Center of Research Excellence program","award":["41\/11"],"award-info":[{"award-number":["41\/11"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Eukaryotic translation initiation factor 2B (<jats:styled-content style=\"fixed-case\">eIF<\/jats:styled-content>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 (<jats:styled-content style=\"fixed-case\">VWM<\/jats:styled-content>) disease, a recessive genetic deadly illness caused by progressive loss of white matter in the brain. In this study we used fibroblasts, which are not involved in the disease, to demonstrate the involvement of <jats:styled-content style=\"fixed-case\">eIF<\/jats:styled-content>2B in mitochondrial function and abundance. Mass spectrometry of total proteome of mouse embryonic fibroblasts (<jats:styled-content style=\"fixed-case\">MEF<\/jats:styled-content>s) isolated from Eif2b5<jats:sup>R132H\/R132H<\/jats:sup> mice revealed unbalanced stoichiometry of proteins involved in oxidative phosphorylation and of mitochondrial translation machinery components, among others. Mutant <jats:styled-content style=\"fixed-case\">MEF<\/jats:styled-content>s exhibit 55% decrease in oxygen consumption rate per mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> content and 47% increase in mitochondrial abundance (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.005), reflecting adaptation to energy requirements. A more robust <jats:styled-content style=\"fixed-case\">eIF<\/jats:styled-content>2B\u2010associated oxidative respiration deficiency was found in mutant primary astrocytes, which exhibit &gt;\u00a03\u2010fold lower <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\u2010linked respiration per cell despite a 2\u2010fold increase in mt<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> content (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.03). The 2\u2010fold increase in basal and stimulated glycolysis in mutant astrocytes (<jats:italic>p<\/jats:italic>\u00a0\u2264\u00a00.03), but not in <jats:styled-content style=\"fixed-case\">MEF<\/jats:styled-content>s, demonstrates their higher energetic needs and further explicates their involvement in the disease. The data demonstrate the critical role of <jats:styled-content style=\"fixed-case\">eIF<\/jats:styled-content>2B in tight coordination of expression from nuclear and mitochondrial genomes and illuminates the importance of mitochondrial function in <jats:styled-content style=\"fixed-case\">VWM<\/jats:styled-content> pathology. Further dissection of the signaling network associated with <jats:styled-content style=\"fixed-case\">eIF<\/jats:styled-content>2B function will help generating therapeutic strategies for <jats:styled-content style=\"fixed-case\">VWM<\/jats:styled-content> disease and possibly other neurodegenerative disorders.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14024-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14024","type":"journal-article","created":{"date-parts":[[2017,3,17]],"date-time":"2017-03-17T14:23:02Z","timestamp":1489760582000},"page":"694-707","source":"Crossref","is-referenced-by-count":48,"title":["Mutant <scp>eIF<\/scp>2B leads to impaired mitochondrial oxidative phosphorylation in vanishing white matter disease"],"prefix":"10.1111","volume":"141","author":[{"given":"Gali","family":"Raini","sequence":"first","affiliation":[{"name":"Department of Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reut","family":"Sharet","sequence":"additional","affiliation":[{"name":"Department of Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melisa","family":"Herrero","sequence":"additional","affiliation":[{"name":"Department of Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Atzmon","sequence":"additional","affiliation":[{"name":"Department of Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjana","family":"Shenoy","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Geiger","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3716-1540","authenticated-orcid":false,"given":"Orna","family":"Elroy\u2010Stein","sequence":"additional","affiliation":[{"name":"Department of Cell Research and Immunology George S. 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