{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:36:16Z","timestamp":1781631376810,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH-funded grants","doi-asserted-by":"publisher","award":["U01NS106845-01A1"],"award-info":[{"award-number":["U01NS106845-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH-funded grants","doi-asserted-by":"publisher","award":["RC 2017-2020"],"award-info":[{"award-number":["RC 2017-2020"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Health Ministry","award":["U01NS106845-01A1"],"award-info":[{"award-number":["U01NS106845-01A1"]}]},{"name":"Italian Health Ministry","award":["RC 2017-2020"],"award-info":[{"award-number":["RC 2017-2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aicardi\u2013Gouti\u00e8res syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in RNASEH2B and RNASEH2A genes. Lymphoblastoid cell lines (LCLs) from RNASEH2A- and RNASEH2B-mutated patients and healthy control were used. Transmission Electron Microscopy (TEM) and flow cytometry were used to assess morphological alterations, reactive oxygen species (ROS) production and mitochondrial membrane potential variations. Seahorse Analyzer was used to investigate metabolic alterations, and mtDNA oxidation and VDAC1 oligomerization were assessed by immunofluorescence. Western blot and RT-qPCR were used to quantify mtTFA protein and mtDNA release. Morphological alterations of mitochondria were observed in both mutated LCLs, and loss of physiological membrane potential was mainly identified in RNASEH2A LCLs. ROS production and 8-oxoGuanine levels were increased in RNASEH2B LCLs. Additionally, the VDAC1 signal was increased, suggesting a mitochondrial pore formation possibly determining mtDNA release. Indeed, higher cytoplasmic mtDNA levels were found in RNASEH2B LCLs. Metabolic alterations confirmed mitochondrial damage in both LCLs. Data highlighted mitochondrial alterations in AGS patients\u2019 LCLs suggesting a pivotal role in AGS pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms232214482","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T02:59:22Z","timestamp":1669085962000},"page":"14482","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Characterization of Mitochondrial Alterations in Aicardi\u2013Gouti\u00e8res Patients Mutated in RNASEH2A and RNASEH2B Genes"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7608-3306","authenticated-orcid":false,"given":"Francesca","family":"Dragoni","sequence":"first","affiliation":[{"name":"Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy"},{"name":"Molecular Biology and Transcriptomics Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9885-1369","authenticated-orcid":false,"given":"Jessica","family":"Garau","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Centre, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5061-683X","authenticated-orcid":false,"given":"Daisy","family":"Sproviero","sequence":"additional","affiliation":[{"name":"IFOM\u2014The FIRC Institute of Molecular Oncology, 20139 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8947-9342","authenticated-orcid":false,"given":"Simona","family":"Orcesi","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5645-021X","authenticated-orcid":false,"given":"Costanza","family":"Varesio","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"De Siervi","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-6907","authenticated-orcid":false,"given":"Stella","family":"Gagliardi","sequence":"additional","affiliation":[{"name":"Molecular Biology and Transcriptomics Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9571-0862","authenticated-orcid":false,"given":"Cristina","family":"Cereda","sequence":"additional","affiliation":[{"name":"Department of Women, Mothers and Neonatal Care, Children\u2019s Hospital \u201cV. Buzzi\u201d, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-0612","authenticated-orcid":false,"given":"Orietta","family":"Pansarasa","sequence":"additional","affiliation":[{"name":"Cellular Model and Neuroepigenetics Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/dmcn.14268","article-title":"Treatments in Aicardi-Gouti\u00e8res syndrome","volume":"62","author":"Crow","year":"2020","journal-title":"Dev. Med. 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