{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T23:18:45Z","timestamp":1791674325746,"version":"4.3.4"},"reference-count":59,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["F31 DK118881"],"award-info":[{"award-number":["F31 DK118881"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008510","name":"University of Maryland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007472","name":"University of Kentucky","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007472","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Somatic differences in mitochondrial DNA (mtDNA) have been observed with aging and between brain regions for mutations, structural variation, and abundance, which are represented by single nucleotide variants (SNVs), large deletions, and copy number, respectively. We used bioinformatic methods to interrogate mtDNA changes and their relation to cortical and cerebellar aging using whole genome sequencing data from the North American Brain Expression Consortium. This dataset contained 292 unpaired postmortem samples from frontal cortex (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009143) and cerebellum (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009149), ranging in age from 0.4 to 100\u2009years and without neurological diagnoses (i.e., controls). Our analyses included (a) evaluation of mtDNA copy number using fastMitoCalc; (b) quantification of large mtDNA deletions using Splice\u2010Break2; (c) analysis of homoplasmic and heteroplasmic SNVs; and (d) mitochondrial genome\u2010wide associations between SNVs and large deletions. For mtDNA deletions specifically, we expanded our previous analyses to include the predicted effects on mitochondrial complexes (I\u2013V), mitochondrial\u2010derived microproteins, and tRNAs. MtDNA copy number significantly decreased in the cortex with age. MtDNA deletions increased in both brain regions with age, with a more dramatic slope in the cortex. These large deletions had significantly more effect on mitochondrial Complex I than other mitochondrial\u2010encoded complexes (III\u2013V); likewise, deletions had significantly more effect on mtALTND4 and SHMOOSE than other annotated microproteins. Heteroplasmic SNVs increased with age in cortex but not cerebellum. Finally, three common SNVs (T14798C, G12372A, and C14766T) significantly associated with large mtDNA deletions (7816\u201314,807, 12,369\u201314,004, and 8775\u201314,771) and altered the length of the repeat sequence associated with the 5\u2032 or 3\u2032 breakpoint.\n                  <\/jats:p>","DOI":"10.1111\/acel.70340","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:45:04Z","timestamp":1766501104000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mitochondrial\n                    <scp>DNA<\/scp>\n                    Variation in the Aging Human Cerebral Cortex and Cerebellum"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-1417","authenticated-orcid":false,"given":"Audrey A.","family":"Omidsalar","sequence":"first","affiliation":[{"name":"Department of Translational Genomics, Keck School of Medicine University of Southern California  California Los Angeles USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Tyrpak","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Keck School of Medicine University of Southern California  California Los Angeles USA"},{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences University of Southern California  California Los Angeles USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Andrew","family":"MacKay","sequence":"additional","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences University of Southern California  California Los Angeles USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin","family":"Yen","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinchas","family":"Cohen","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geidy","family":"Serrano","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute (BSHRI)  Sun City Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute (BSHRI)  Sun City Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Nalls","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics National Institute on Aging, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dena G.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics National Institute on Aging, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Cookson","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics National Institute on Aging, National Institutes of Health  Bethesda Maryland USA"},{"name":"Center for Alzheimer's and Related Dementias National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Singleton","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics National Institute on Aging, National Institutes of Health  Bethesda Maryland USA"},{"name":"Center for Alzheimer's and Related Dementias National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Raphael","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics National Institute on Aging, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"North American Brain Expression Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke E.","family":"Hjelm","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Keck School of Medicine University of Southern California  California Los Angeles USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/13779"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2416433122"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005836"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458513490547"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1292\u2010324"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16113"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giab008"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102164\u201015\u2010677"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858415585108"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873\u20103468.14021"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2005.06.008"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.02.009"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2010.11.016"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000952"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2009.03.003"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14296"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1159\/000528051"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz164"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201041785\u20107"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky780"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/2191\u2010219X\u20102\u201063"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archger.2010.11.019"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010021\u201000495\u20108"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mocell.2024.100139"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201031122\u20100"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2021.07.004"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0228166"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi0123s44"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3229"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0921\u20108777(99)00028\u20102"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010022\u201001769\u20103"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI158447"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu825"},{"key":"e_1_2_10_36_1","unstructured":"Ogle D. 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