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We differentiated iPSCs to heteroplasmic human cells and tissues with isogenic nuclear background and show that the disease manifestation depends on cellular context. We show that upon neuronal differentiation, complex I is actively degraded by an autophagy-mediated mechanism. Our data indicate that cellular context actively modifies mtDNA segregation and manifestations, and that complex I is actively down-regulated in neurons with m.3243A&gt;G mutation.<\/jats:p>","DOI":"10.1073\/pnas.1311660110","type":"journal-article","created":{"date-parts":[[2013,9,3]],"date-time":"2013-09-03T21:58:16Z","timestamp":1378245496000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":198,"title":["Tissue- and cell-type\u2013specific manifestations of heteroplasmic mtDNA 3243A&gt;G mutation in human induced pluripotent stem cell-derived disease model"],"prefix":"10.1073","volume":"110","author":[{"given":"Riikka H.","family":"H\u00e4m\u00e4l\u00e4inen","sequence":"first","affiliation":[{"name":"Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuula","family":"Manninen","sequence":"additional","affiliation":[{"name":"Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Koivum\u00e4ki","sequence":"additional","affiliation":[{"name":"Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Kislin","sequence":"additional","affiliation":[{"name":"Neuroscience Center, University of Helsinki, 00790, Helsinki, Finland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Otonkoski","sequence":"additional","affiliation":[{"name":"Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anu","family":"Suomalainen","sequence":"additional","affiliation":[{"name":"Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland;"},{"name":"Department of Neurology, Helsinki University Central Hospital, 00290, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,9,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awg170"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.07.004"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/331717a0"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3201231"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3109\/07853890.2011.598547"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/348651a0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2006.12.004"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/301959"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0892-368"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410160409"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1177\/088307389400900102"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2004.01.002"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.42.3.545"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410310408"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2008.02.001"},{"key":"e_1_3_3_16_2","first-page":"934","article-title":"The mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): Genetic, biochemical, and morphological correlations in skeletal muscle","volume":"50","author":"Moraes CT","year":"1992","unstructured":"CT Moraes, E Ricci, E Bonilla, S DiMauro, EA Schon, The mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): Genetic, biochemical, and morphological correlations in skeletal muscle. 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