{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:47:53Z","timestamp":1787161673573,"version":"build-2736575974"},"reference-count":61,"publisher":"National Academy of Sciences","issue":"40","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009282","name":"United Mitochondrial Disease Foundation","doi-asserted-by":"publisher","award":["no number"],"award-info":[{"award-number":["no number"]}],"id":[{"id":"10.13039\/100009282","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["5R01AG078814"],"award-info":[{"award-number":["5R01AG078814"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["5R01CA259635"],"award-info":[{"award-number":["5R01CA259635"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,10,7]]},"abstract":"<jats:p>\n                    MEPAN (\n                    <jats:underline>M<\/jats:underline>\n                    itochondrial\n                    <jats:underline>E<\/jats:underline>\n                    noyl CoA Reductase\n                    <jats:underline>P<\/jats:underline>\n                    rotein-\n                    <jats:underline>A<\/jats:underline>\n                    ssociated\n                    <jats:underline>N<\/jats:underline>\n                    eurodegeneration) is an early-onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here, we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the\n                    <jats:italic toggle=\"yes\">Mecr<\/jats:italic>\n                    gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC\u2013MS\/MS-based proteomic analysis of\n                    <jats:italic toggle=\"yes\">Mecr<\/jats:italic>\n                    mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron\u2013sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM-mediated supercomplex modulation and ISC biogenesis and suggest unique pathways for therapeutics.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2506761122","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T19:10:52Z","timestamp":1759173052000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron\u2013sulfur cluster and supercomplex formation"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0843-2126","authenticated-orcid":false,"given":"Deborah G.","family":"Murdock","sequence":"first","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]},{"name":"Department of Pediatrics, Division of Human Genetics, The Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin A.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kierstin","family":"Keller","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine L.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maina","family":"Beauplan","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Human Genetics, The Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia"]},{"name":"Neurobehavior Testing Core, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"D\u2019Alessandro","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Haltom","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7480-8278","authenticated-orcid":false,"given":"Douglas C.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia","place":["Philadelphia"]},{"name":"Department of Pediatrics, Division of Human Genetics, The Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"e_1_3_4_1_2","article-title":"MECR-Related neurologic disorder","author":"Heimer G.","year":"1993","unstructured":"G. Heimer, A. Gregory, P. Hogarth, S. Hayflick, B. Ben Zeev, MECR-Related neurologic disorder. GeneReviews 31070877 (1993).","journal-title":"GeneReviews"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.09.021"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2023-109340"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2024.104917"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1688767"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(03)00038-X"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302851200"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.18.6243-6253.2001"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx105"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-021-00951-3"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3514-17.2018"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(91)80955-3"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19754"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.6b01005"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1702849114"},{"key":"e_1_3_4_16_2","first-page":"1913","article-title":"2017) Acyl modification and binding of mitochondrial ACP to multiprotein complexes","volume":"10","author":"Angerer H.","year":"1864","unstructured":"H. Angerer , 2017) Acyl modification and binding of mitochondrial ACP to multiprotein complexes. Biochim. Biophys. Acta Mol. Cell Res. 10, 1913\u20131920 (1864).","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.8b00184"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.9b00539"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09989-y"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20130116"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2025597118"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.06.039"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8MD00489G"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58041"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36358-7"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151171"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00873-0"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00313188"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.10.072"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(98)00461-2"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2014.29.2.185"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806991200"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047196"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M701486200"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2023.1147784"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17828"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20140239"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)52372-3"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-018-0073-1"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA119.001784"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.04.021"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102164"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009557200"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E17-09-0555"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.06.033"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00956-y"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01497-1"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600905"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.032"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2010.01.014"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.03.029"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.03.045"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.240021"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-019-0208-x"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07488-9"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9740-4_13"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.115.176594"},{"key":"e_1_3_4_58_2","first-page":"Unit","article-title":"Simple behavioral assessment of mouse olfaction","volume":"8","author":"Yang M.","year":"2009","unstructured":"M. Yang, J. N. Crawley, Simple behavioral assessment of mouse olfaction. Curr. Protoc. Neurosci. 8, Unit\u20138.24 (2009).","journal-title":"Curr. Protoc. Neurosci."},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1097\/IIO.0000000000000303"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470942390.mo150182"},{"key":"e_1_3_4_61_2","unstructured":"K. A. Janssen A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron sulfur cluster and supercomplex formation. MassIVE. https:\/\/massive.ucsd.edu\/ProteoSAFe\/dataset.jsp?accession=MSV000099206. Deposited 16 September 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2506761122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T19:11:47Z","timestamp":1759173107000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2506761122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":61,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2025,10,7]]}},"alternative-id":["10.1073\/pnas.2506761122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2506761122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]},"assertion":[{"value":"2025-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2506761122"}}