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
In the process of oxidative phosphorylation, protons are pumped into the intermembrane space to establish the mitochondrial membrane potential (MMP). Relying on the electrochemical gradient, protons can return to the ...In the process of oxidative phosphorylation, protons are pumped into the intermembrane space to establish the mitochondrial membrane potential (MMP). Relying on the electrochemical gradient, protons can return to the matrix through the ATP synthase complex with ATP generation. MitoQ, a lipophilic cation drug, can be bsorbed to the inner mitochondrial membrane with the cationic moiety staying at the intermembrane space[1].展开更多
There were signi cant differences in energy metabolism between normal and tumor cells(normal cells depend on mitochondrial respiration for energy supply,while tumor cells rely on aerobic glycolysis)^([1,2]).Based on t...There were signi cant differences in energy metabolism between normal and tumor cells(normal cells depend on mitochondrial respiration for energy supply,while tumor cells rely on aerobic glycolysis)^([1,2]).Based on this difference,this study aims to provide a new therapeutic strategy for precise radiation protection of normal cells through utilizing selective autophagy induced by MitoQ-constructed pseudo-mitochondrial membrane potential(PMMP)by targeting mitochondrial respiration.Normal cells HA.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Key Program of National Natural Science Foundation of China (U1432248), National Natural Science Foundation of China (11505245), Western Talent Program of Chinese Academy of Sciences (Y460040XB0)
文摘In the process of oxidative phosphorylation, protons are pumped into the intermembrane space to establish the mitochondrial membrane potential (MMP). Relying on the electrochemical gradient, protons can return to the matrix through the ATP synthase complex with ATP generation. MitoQ, a lipophilic cation drug, can be bsorbed to the inner mitochondrial membrane with the cationic moiety staying at the intermembrane space[1].
基金Fellow of Youth Innovation Promotion Association(2020414)Key Program of Natural Science Foundation of Gansu Province(21JR7RA097)。
文摘There were signi cant differences in energy metabolism between normal and tumor cells(normal cells depend on mitochondrial respiration for energy supply,while tumor cells rely on aerobic glycolysis)^([1,2]).Based on this difference,this study aims to provide a new therapeutic strategy for precise radiation protection of normal cells through utilizing selective autophagy induced by MitoQ-constructed pseudo-mitochondrial membrane potential(PMMP)by targeting mitochondrial respiration.Normal cells HA.
