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Autoantibodies (NMO\u2010IgG) against the water channel protein, aquaporin 4 (AQP4), are a serologic marker in NMO patients, and they are known to be responsible for the pathophysiology of the disease. In the brain, AQP4 is mainly expressed in astrocytes, especially at the end\u2010feet, where they form the blood\u2010brain barrier. Following the interaction between NMO\u2010IgG and AQP4 in astrocytes, rapid AQP4 endocytosis initiates pathogenesis. However, the cellular and molecular mechanisms of astrocyte destruction by autoantibodies remain largely elusive. We established an in vitro human astrocyte model system using induced pluripotent stem cells (iPSCs) technology in combination with NMO patient\u2010derived serum and IgG to elucidate the cellular and functional changes caused by NMO\u2010IgG. Herein, we observed that NMO\u2010IgG induces structural alterations in mitochondria and their association with the endoplasmic reticulum (ER) and lysosomes at the ultrastructural level, which potentially leads to impaired mitochondrial functions and dynamics. Indeed, human astrocytes display impaired mitochondrial bioenergetics and autophagy activity in the presence of NMO\u2010IgG. We further demonstrated NMO\u2010IgG\u2010driven ER membrane deformation into a multilamellar structure in human astrocytes. Together, we show that NMO\u2010IgG rearranges cellular organelles and alter their functions and that our in vitro system using human iPSCs offers previously unavailable experimental opportunities to study the pathophysiological mechanisms of NMO in human astrocytes or conduct large\u2010scale screening for potential therapeutic compounds targeting astrocytic abnormalities in patients with NMO.<\/jats:p>","DOI":"10.1096\/fj.202100637r","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T13:26:05Z","timestamp":1630329965000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neuromyelitis optica (NMO)\u2010IgG\u2010driven organelle reorganization in human iPSC\u2010derived astrocytes"],"prefix":"10.1096","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2553-6296","authenticated-orcid":false,"given":"Sukhee","family":"Cho","sequence":"first","affiliation":[{"name":"Neural Circuit Research Group Korea Brain Research Institute Daegu South Korea"},{"name":"Department of Brain and Cognitive Sciences DGIST Daegu South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1525-2599","authenticated-orcid":false,"given":"Hyein","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Brain and Cognitive Sciences DGIST Daegu South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minkyo","family":"Jung","sequence":"additional","affiliation":[{"name":"Neural Circuit Research Group Korea Brain Research Institute Daegu South 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Young","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Neurology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6432-6964","authenticated-orcid":false,"given":"Jinsoo","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Brain and Cognitive Sciences DGIST Daegu South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0820-6233","authenticated-orcid":false,"given":"Ji Young","family":"Mun","sequence":"additional","affiliation":[{"name":"Neural Circuit Research Group Korea Brain Research Institute Daegu South 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