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Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A\u2009&gt;\u2009G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A\u2009&gt;\u2009G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPR<jats:sup>mt<\/jats:sup>), together with reduced Wnt\/\u03b2-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPR<jats:sup>mt<\/jats:sup>, improved mitochondrial function, restored expression of <jats:italic>GSK3B<\/jats:italic> and <jats:italic>WNT7B<\/jats:italic>, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPR<jats:sup>mt<\/jats:sup> could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A\u2009&gt;\u2009G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.<\/jats:p>","DOI":"10.1038\/s41419-021-03993-1","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T10:03:06Z","timestamp":1626256986000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["ATF5, a putative therapeutic target for the mitochondrial DNA 3243A\u2009&gt;\u2009G mutation-related disease"],"prefix":"10.1038","volume":"12","author":[{"given":"Xinpei","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinfeng","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengwen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehua","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Eve","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congrong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"3993_CR1","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1172\/JCI61398","volume":"123","author":"DC Wallace","year":"2013","unstructured":"Wallace DC. 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