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Mitochondria\u2010associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for many biological pathways, such as autophagy and mitochondria fission and fusion. This study aimed to alleviate the effects of hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>)\u2010induced persistent PARP\u20101 activation and MAM dysregulation by the usage of a PARP\u20101 inhibitor. Results showed that receptor\u2010interacting protein kinase (RIPK) 1 inhibitor (necrostatin\u20101) and PARP\u20101 inhibitor (olaparib) protected retinal precursor cells from H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced death, while a pan\u2010caspase inhibitor (Z\u2010VAD\u2010FMK) failed to protect R28 cells. Olaparib also alleviated H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced MAM dysregulation, as evidenced by decreased VDAC1\/ITPR3 interactions and reduced mitochondrial membrane potential collapse. Additionally, olaparib also inhibited H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced autophagy. Inhibiting autophagic flux increased MAM signaling under both normal and oxidative conditions. Furthermore, H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> treatment caused a reduction in the protein level of mitofusin\u20102 (MFN2) in a dose\u2010 and time\u2010dependent manner. <jats:italic>Mfn2<\/jats:italic> knockdown was found to further magnify MAM dysregulation and mitochondrial dysfunction under normal and oxidative conditions. <jats:italic>Mfn2<\/jats:italic> overexpression surprisingly enhanced H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced MAM signaling and failed to rescue H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced mitochondrial dysfunction. These results indicate that MAMs probably serve as a membrane source for oxidative stress\u2010associated autophagy. MAM dysregulation also contributed to H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced PARP\u20101\u2010dependent cell death. However, more studies are required to decipher the link between the modulation of <jats:italic>Mfn2<\/jats:italic> expression, changes in MAM integrity, and alterations in mitochondrial performances.<\/jats:p>","DOI":"10.1002\/jbt.23303","type":"journal-article","created":{"date-parts":[[2023,1,14]],"date-time":"2023-01-14T06:37:36Z","timestamp":1673678256000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mitochondria\u2010associated endoplasmic reticulum membranes dysfunction contributes to PARP\u20101\u2010dependent cell death under oxidative stress in retinal precursor cells"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6897-3130","authenticated-orcid":false,"given":"Yuting","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology &amp; Visual Science, Eye &amp; ENT Hospital, Shanghai Medical College Fudan University Shanghai 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