Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucia...Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.展开更多
Dexamethasone—a potent synthetic glucocorticoid—has multiple diagnostic and therapeutic applications in wide range of age groups. However, the side-effects of dexamethasone (Dex) treatment including those on develop...Dexamethasone—a potent synthetic glucocorticoid—has multiple diagnostic and therapeutic applications in wide range of age groups. However, the side-effects of dexamethasone (Dex) treatment including those on development are becoming increasingly apparent. Since the developmental processes are energy-dependent, we examined the effects of chronic Dex treatment on kinetics properties of liver mitochondrial F0.F1-ATPase and mitochondrial membrane lipid profiles in rats belonging to different developmental age groups (2, 3, 4 and 5 weeks) and in adults (~8 weeks). The animals were treated with a subcutaneous dose of 2 mg of Dex/kg body weight (or saline as vehicle) for three alternative days (at around 7.00 A.M.) prior to the day of sacrifice. Dex treatment resulted in significant reduction in F0.F1-ATPase activity in developmental age groups and in adults as compared to their age-matched vehicle-treated control group. The substrate kinetics analysis of F0.F1-ATPase resolved Km and Vmax values in 3 components in all the control age groups;whereas Dex treatment significantly altered the Km and Vmax values or abolished the entire components in age-specific manner. Dex treatment significantly lowered the energy of activation and altered phase transition temperature (TtoC) in all the developmental age groups and in adults. Dex treatment significantly increased the contents of total phospholipid (TPL), individual phospholipids classes and cholesterol (CHL) in all the developmental age groups whereas opposite pattern was observed in adults. The mitochondrial membrane became more fluidized in the developing age groups (2, 4 and 5 weeks);whereas no change was observed in 3-week and adult groups following Dex treatment. In present study, our data demonstrate comprehensive deleterious effects of chronic Dex treatment on liver mitochondrial membrane structure and F0.F1-ATPase functional properties with respect to energy metabolism. At the same time, our data also warns against excessive repeated use of antenatal DEX in treatments in growing and adult human patients.展开更多
基金supported by the National Natural Science Foundation of China(Youth Program),No.81901282(to XC)the National Natural Science Foundation of China,Nos.81401416(to PX),81870992(to PX),81870856(to XC and MZ)+3 种基金Guangdong Basic and Applied Basic Research Foundation the Science Foundation,No.2019A1515011189(to XC)Central Government Guiding Local Science and Technology Development Projects,No.ZYYD2022C17(to PX)Key Project of Guangzhou Health Commission,No.2019-ZD-09(to PX)Science and Technology Planning Project of Guangzhou,Nos.202102020029(to XC),202102010010(to PX)。
文摘Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.
文摘Dexamethasone—a potent synthetic glucocorticoid—has multiple diagnostic and therapeutic applications in wide range of age groups. However, the side-effects of dexamethasone (Dex) treatment including those on development are becoming increasingly apparent. Since the developmental processes are energy-dependent, we examined the effects of chronic Dex treatment on kinetics properties of liver mitochondrial F0.F1-ATPase and mitochondrial membrane lipid profiles in rats belonging to different developmental age groups (2, 3, 4 and 5 weeks) and in adults (~8 weeks). The animals were treated with a subcutaneous dose of 2 mg of Dex/kg body weight (or saline as vehicle) for three alternative days (at around 7.00 A.M.) prior to the day of sacrifice. Dex treatment resulted in significant reduction in F0.F1-ATPase activity in developmental age groups and in adults as compared to their age-matched vehicle-treated control group. The substrate kinetics analysis of F0.F1-ATPase resolved Km and Vmax values in 3 components in all the control age groups;whereas Dex treatment significantly altered the Km and Vmax values or abolished the entire components in age-specific manner. Dex treatment significantly lowered the energy of activation and altered phase transition temperature (TtoC) in all the developmental age groups and in adults. Dex treatment significantly increased the contents of total phospholipid (TPL), individual phospholipids classes and cholesterol (CHL) in all the developmental age groups whereas opposite pattern was observed in adults. The mitochondrial membrane became more fluidized in the developing age groups (2, 4 and 5 weeks);whereas no change was observed in 3-week and adult groups following Dex treatment. In present study, our data demonstrate comprehensive deleterious effects of chronic Dex treatment on liver mitochondrial membrane structure and F0.F1-ATPase functional properties with respect to energy metabolism. At the same time, our data also warns against excessive repeated use of antenatal DEX in treatments in growing and adult human patients.
