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A primary defect in Wolfram syndrome involves poor ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP\n                    <jats:sub>3<\/jats:sub>\n                    R-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transfer from ER to mitochondria and decreased mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake. In turn, reduced mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    content inhibits mitochondrial ATP production leading to an increased NADH\/NAD\n                    <jats:sup>+<\/jats:sup>\n                    ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis, enhance mitochondrial function and improve neuronal health.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-50502-x","type":"journal-article","created":{"date-parts":[[2024,7,21]],"date-time":"2024-07-21T06:01:18Z","timestamp":1721541678000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6203-4810","authenticated-orcid":false,"given":"Mailis","family":"Liiv","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0296-8325","authenticated-orcid":false,"given":"Annika","family":"Vaarmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4188-4207","authenticated-orcid":false,"given":"Dzhamilja","family":"Safiulina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1953-5692","authenticated-orcid":false,"given":"Vinay","family":"Choubey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruby","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malle","family":"Kuum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5429-0363","authenticated-orcid":false,"given":"Lucia","family":"Janickova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Hodurova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8044-8419","authenticated-orcid":false,"given":"Michal","family":"Cagalinec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akbar","family":"Zeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3363-8583","authenticated-orcid":false,"given":"Miriam A.","family":"Hickey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0980-4828","authenticated-orcid":false,"given":"Yi-Long","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Gogichaishvili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merle","family":"Mandel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Plaas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5226-345X","authenticated-orcid":false,"given":"Eero","family":"Vasar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Loncke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Vervliet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Fen","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5968-4828","authenticated-orcid":false,"given":"Geert","family":"Bultynck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Veksler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4850-3198","authenticated-orcid":false,"given":"Allen","family":"Kaasik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,21]]},"reference":[{"key":"50502_CR1","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1097\/MOP.0b013e328354ccdf","volume":"24","author":"L Rigoli","year":"2012","unstructured":"Rigoli, L. & Di Bella, C. 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