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ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease
Authors:Xinpei Gao  Zhixin Jiang  Xinfeng Yan  Jiping Liu  Fengwen Li  Peng Liu  Jialu Li  Yuehua Wei  Yi Eve Sun  Yinan Zhang  Congrong Wang
Abstract:The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPRmt), together with reduced Wnt/β-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPRmt, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPRmt could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.Subject terms: Mechanisms of disease, Diabetes
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