The mitochondrial 3243A>G mutation(m.3243A>G)is associated with diverse clinical phenotypes.To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients,urine-derived stem ...The mitochondrial 3243A>G mutation(m.3243A>G)is associated with diverse clinical phenotypes.To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients,urine-derived stem cells(USCs)and a mitochondrial leucyl-tRNA synthetase gene(lars-2)deficient Caenorhabditis elegans(C.elegans)model are used to assess mitochondrial homeostasis and neuromuscular dysfunction.Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function,disrupted mitochondrial dynamics,and inhibited mitophagy,which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase(OMA1)-induced mitochondrial phosphatase and tensin(PTEN)induced kinase 1(PINK1)degradation.Furthermore,lars-2 knockdown in C.elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation.MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway.These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.展开更多
Osteoporosis is a debilitating bone disease affecting millions of people. Here, we used human urine-derived stem cells(USCs),which were noninvasively harvested from unlimited and easily available urine, as a "fac...Osteoporosis is a debilitating bone disease affecting millions of people. Here, we used human urine-derived stem cells(USCs),which were noninvasively harvested from unlimited and easily available urine, as a "factory" to obtain extracellular vesicles(USCEVs) and demonstrated that the systemic injection of USC-EVs effectively alleviates bone loss and maintains bone strength in osteoporotic mice by enhancing osteoblastic bone formation and suppressing osteoclastic bone resorption. More importantly, the anti-osteoporotic properties of USC-EVs are not notably disrupted by the age, gender, or health condition(with or without osteoporosis) of the USC donor. Mechanistic studies determined that collagen triple-helix repeat containing 1(CTHRC1) and osteoprotegerin(OPG) proteins are enriched in USC-EVs and required for USC-EV-induced pro-osteogenic and anti-osteoclastic effects. Our results suggest that autologous USC-EVs represent a promising novel therapeutic agent for osteoporosis by promoting osteogenesis and inhibiting osteoclastogenesis by transferring CTHRC1 and OPG.展开更多
基金funded by the NIH Office of Research Infrastructure Programs(P40 OD010440)supported by the National Natural Science Foundation of China(82471893 and 82070913)+2 种基金Key discipline project of Hongkou District Health Commission(HKLCFC202403)Tongji Hospital Start-up Funding for Scientific Research(RCQD2301)Research fund from Shanghai Fourth People's Hospital(sykyqd01801,SYXKZT-2021-1001).
文摘The mitochondrial 3243A>G mutation(m.3243A>G)is associated with diverse clinical phenotypes.To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients,urine-derived stem cells(USCs)and a mitochondrial leucyl-tRNA synthetase gene(lars-2)deficient Caenorhabditis elegans(C.elegans)model are used to assess mitochondrial homeostasis and neuromuscular dysfunction.Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function,disrupted mitochondrial dynamics,and inhibited mitophagy,which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase(OMA1)-induced mitochondrial phosphatase and tensin(PTEN)induced kinase 1(PINK1)degradation.Furthermore,lars-2 knockdown in C.elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation.MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway.These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.
基金supported by the National Natural Science Foundation of China (Grant nos. 81522012, 81702237, 81670807, 81871822, 81801395, 81600699, 81701383, and 81802138)the Thousand Youth Talents Plan of China (Grant no. D1119003)+8 种基金the Medicine and Health Science and Technology Innovation Project of Chinese Academy of Medical Sciences (Grant no. 2018-I2M-HL-024)the High Level Talent Gathering Project of Hunan Province (Grant nos. 2017XK2039, and 2018RS3029)the Innovation Driven Project of Central South University (Grant nos. 2016CX028,2019CX014, and 2018CX029)the Youth Foundation of Xiangya Hospital in Central South University (Grant no. 2016Q10)the Hunan Provincial Innovation Foundation for Postgraduate (Grant no. CX2018B045)the Fundamental Research Funds for the Central Universities of Central South University (Grant nos. 2017zzts211 and 2018zzts895)the Hunan Province Natural Science Foundation of China (Grant no. 2017JJ3501)the China Postdoctoral Science Foundation (Grant nos. 2017M612596, 2017M622614, and 2018M632998)the Natural Science Foundation for Distinguished Yong Scholars of Guangdong Province (Grant no. 2016A030306051)
文摘Osteoporosis is a debilitating bone disease affecting millions of people. Here, we used human urine-derived stem cells(USCs),which were noninvasively harvested from unlimited and easily available urine, as a "factory" to obtain extracellular vesicles(USCEVs) and demonstrated that the systemic injection of USC-EVs effectively alleviates bone loss and maintains bone strength in osteoporotic mice by enhancing osteoblastic bone formation and suppressing osteoclastic bone resorption. More importantly, the anti-osteoporotic properties of USC-EVs are not notably disrupted by the age, gender, or health condition(with or without osteoporosis) of the USC donor. Mechanistic studies determined that collagen triple-helix repeat containing 1(CTHRC1) and osteoprotegerin(OPG) proteins are enriched in USC-EVs and required for USC-EV-induced pro-osteogenic and anti-osteoclastic effects. Our results suggest that autologous USC-EVs represent a promising novel therapeutic agent for osteoporosis by promoting osteogenesis and inhibiting osteoclastogenesis by transferring CTHRC1 and OPG.
