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The integrity of mitochondria-associated membranes (MAMs), the structure connecting mitochondria and the endoplasmic reticulum (ER), is compromised during aging. This study investigated the effects of aging on MAMs and ER stress in the parotid glands of mice. Here, aged mice presented abnormalities in gland morphology and mitochondrial morphology and reduced MAMs integrity. Protein kinase R-like endoplasmic reticulum kinase (PERK) signaling is the primary mediator of ER stress, which is activated in the parotid glands of aged mice. Furthermore, aging-induced MFN2 downregulation disrupts mitochondrial dynamics. In addition, aging reduces MAMs function by blocking the MFN2\u2013PERK interaction. Treatment with 4-phenylbutyric acid (4-PBA) improved MAMs integrity, inhibited the PERK pathway, and reduced apoptosis. Like 4-PBA, GSK2606414, a pharmacological antagonist of PERK, regulates ER stress and MAMs. Collectively, our data highlight disruption of the MFN2\u2013PERK axis-mediated ER\u2013mitochondrion connection as a cause of aging-induced parotid gland dysfunction.<\/jats:p>","DOI":"10.1177\/00220345261427294","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T08:55:54Z","timestamp":1774688154000},"page":"1643-1654","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["MFN2\u2013PERK Axis Regulates ER Stress in Parotid Glands of Aged Mice via MAMs"],"prefix":"10.1177","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5916-1480","authenticated-orcid":false,"given":"Y.","family":"Chen","sequence":"first","affiliation":[{"name":"Changsha Stomatological Hospital, Changsha, Hunan, China"},{"name":"School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.M.","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China"},{"name":"Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.L.","family":"Zhu","sequence":"additional","affiliation":[{"name":"Changsha Stomatological Hospital, Changsha, Hunan, China"},{"name":"School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.Y.","family":"Shan","sequence":"additional","affiliation":[{"name":"Changsha Stomatological Hospital, Changsha, Hunan, China"},{"name":"School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.G.","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, Xiangya Stomalogical Hospital, Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5803-505X","authenticated-orcid":false,"given":"H.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China"},{"name":"Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"e_1_3_5_2_1","doi-asserted-by":"crossref","unstructured":"Aleksandrova K Koelman L Rodrigues CE. 2021. 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