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To address this gap, we investigated how the function of astrocytes and their ability to support neurons is influenced by PINK1 deficiency. For the first time, we demonstrate that human astrocytes exhibit robust PINK1 activity. Next, the first bulk transcriptomic study of human PINK1 mutant astrocytes was performed followed by biochemical validation at the protein level, uncovering homeostatic collapse. Co-culture experiments demonstrated that this astrocyte dysfunction drives neuronal damage through non-cell-autonomous mechanisms. Notably, pharmacological enhancement of autophagy successfully mitigated this inflammatory secretome, indicating that mitochondrial quality control deficits are reversible. These findings establish an unexpected role for PINK1 in glial biology, reveal that astrocytes are vulnerable to mitophagy deficits, and highlight a novel mechanistic link connecting mitochondrial dysfunction, neuroinflammation, and neurodegeneration.<\/jats:p>","DOI":"10.64898\/2026.06.04.729996","type":"posted-content","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T20:30:11Z","timestamp":1781037011000},"source":"Crossref","is-referenced-by-count":2,"title":["PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4587-8047","authenticated-orcid":false,"given":"Gabriella","family":"Fiorino","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1619-5394","authenticated-orcid":false,"given":"Damian N.","family":"Di Florio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7334-3845","authenticated-orcid":false,"given":"Deshaun H.","family":"Hadley","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4813-756X","authenticated-orcid":false,"given":"Owen A.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1919-9676","authenticated-orcid":false,"given":"Fabienne C.","family":"Fiesel","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1178-3149","authenticated-orcid":false,"given":"Wolfdieter","family":"Springer","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061103350625000_2026.06.04.729996v1.1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2024-080952"},{"key":"2026061103350625000_2026.06.04.729996v1.2","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.3233\/JPD-223380","article-title":"Early-Onset Parkinson\u2019s Disease: Creating the Right Environment for a Genetic Disorder","volume":"12","year":"2022","journal-title":"J Parkinsons Dis"},{"key":"2026061103350625000_2026.06.04.729996v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01513-9"},{"key":"2026061103350625000_2026.06.04.729996v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2015.10.021"},{"key":"2026061103350625000_2026.06.04.729996v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01061-1"},{"key":"2026061103350625000_2026.06.04.729996v1.6","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2286414"},{"key":"2026061103350625000_2026.06.04.729996v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae177"},{"key":"2026061103350625000_2026.06.04.729996v1.8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36470"},{"key":"2026061103350625000_2026.06.04.729996v1.9","doi-asserted-by":"crossref","unstructured":"T. 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