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PRMT8 is primarily expressed in the central nervous system, specifically within the cellular membrane and synaptic vesicles. Recently, PRMT8 has been described to play key roles in neuronal signaling such as a regulator of dendritic arborization, synaptic function and maturation, and neuronal differentiation and plasticity. Here, we examined the role of PRMT8 in response to hypoxia\u2010induced stress in brain metabolism. Our results from liquid chromatography mass spectrometry, mitochondrial oxygen consumption rate, and protein analyses indicate that PRMT8(\u2212\/\u2212) knockout mice presented with altered membrane phospholipid composition, decreased mitochondrial stress capacity, and increased neuroinflammatory markers, such as tumor necrosis factor alpha and ionized calcium binding adaptor molecule 1 (Iba1, a specific marker for microglia\/macrophage activation) after hypoxic stress. Furthermore, adenovirus\u2010based overexpression of PRMT8 reversed the changes in membrane phospholipid composition, mitochondrial stress capacity, and neuroinflammatory markers. Together, our findings establish PRMT8 as an important regulatory component of membrane phospholipid composition, short\u2010term memory function, mitochondrial function, and neuroinflammation in response to hypoxic stress.<\/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\/jnc15462-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15462","type":"journal-article","created":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T08:56:57Z","timestamp":1625302617000},"page":"742-761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Protein arginine methyltransferase 8 modulates mitochondrial bioenergetics and 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Health Sciences Center  Shreveport LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reggie H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology Louisiana State University Health Sciences Center  Shreveport LA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer I.","family":"Brown","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences The University of British Columbia  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Frankel","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences The University of British Columbia  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-5423","authenticated-orcid":false,"given":"Hung W.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy 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