{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:55:17Z","timestamp":1792068917905,"version":"4.4.0"},"reference-count":31,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"10","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,3,7]]},"abstract":"<jats:p>\n                    Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    -mutant organoids, with some de novo mtSNVs likely due to the\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adr0690","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T13:59:41Z","timestamp":1741355981000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["Origin and cell type specificity of mitochondrial DNA mutations in\n                    <i>C9ORF72<\/i>\n                    ALS-FTLD human brain organoids"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7670-6411","authenticated-orcid":true,"given":"Yu","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK."},{"name":"Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korn\u00e9lia","family":"Szeb\u00e9nyi","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea M. D.","family":"Wenger","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1301-2292","authenticated-orcid":true,"given":"Andr\u00e1s","family":"Lakatos","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7065-6617","authenticated-orcid":true,"given":"Patrick F.","family":"Chinnery","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK."},{"name":"Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.02.006"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06331-w"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-01989-y"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddad161"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-022-02423-6"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1247125"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00923-4"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09026-y"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao4426"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010573"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.12.008"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3966"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13548"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009242"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature20413"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-023-01526-9"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1722"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-39574-9"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells10020249"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314085111"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2625-x"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2017.06.011"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02673-7"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44192-0"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007529"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu483"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0645-6"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20921"},{"key":"e_1_3_2_31_2","first-page":"e63870","article-title":"Measuring single-cell mitochondrial DNA copy number and heteroplasmy using digital droplet polymerase chain reaction","volume":"185","author":"Burr S. P.","year":"2022","unstructured":"S. P. Burr, P. F. Chinnery, Measuring single-cell mitochondrial DNA copy number and heteroplasmy using digital droplet polymerase chain reaction. JoVE 185, e63870 (2022).","journal-title":"JoVE"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25482-x"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adr0690","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T14:01:25Z","timestamp":1741788085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adr0690"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,7]]},"references-count":31,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,3,7]]}},"alternative-id":["10.1126\/sciadv.adr0690"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adr0690","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,7]]},"assertion":[{"value":"2024-06-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadr0690"}}