By controlling the proper folding of proteins imported into mitochondria and ensuring crosstalk between the reticulum and mitochondria to modulate intra cellular calcium fluxes.Mortalin is a chaperone protein that pla...By controlling the proper folding of proteins imported into mitochondria and ensuring crosstalk between the reticulum and mitochondria to modulate intra cellular calcium fluxes.Mortalin is a chaperone protein that plays crucial roles in neuronal homeostasis and activity.Howeve r,its expression and stability are strongly modified in response to cellular stresses,in particular upon alte red oxidative conditions during neurodegeneration.Here,we report and discuss the abundant literature that has highlighted its contribution to the pathophysiology of Parkinson's disease,as well as its therapeutic and prognostic potential in this still incurable pathology.展开更多
Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells.Mitochondrial dynamics balance is exactly regulated by molecular motor consi...Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells.Mitochondrial dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton proteins.Thus,targeting myosin eactin molecular motor is considered as a promising strategy for anti-cancer.In this study,we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics via pharmacologically targeting molecular motor.Here,we found J13 could directly target myosin-9(MYH9)eactin molecular motor to promote mitochondrial fission progression,and markedly inhibited cancer cells survival,proliferation and migration.Mechanism study revealed that J13 impaired MYH9 eactin interaction to inactivate molecular motor,and caused a cytoskeleton-dependent mitochondrial dynamics imbalance.Moreover,stable isotope labeling with amino acids in cell culture(SILAC)technology-coupled with pulldown analysis identified HSPA9 as a crucial adaptor protein connecting MYH9 eactin molecular motor to mitochondrial fission.Taken together,we reported the first natural small-molecule directly targeting MYH9 eactin molecular motor for anti-cancer translational research.Besides,our study also proved the conceptual practicability of pharmacologically disrupting mitochondrial fission/fusion dynamics in human cancer therapy.展开更多
文摘By controlling the proper folding of proteins imported into mitochondria and ensuring crosstalk between the reticulum and mitochondria to modulate intra cellular calcium fluxes.Mortalin is a chaperone protein that plays crucial roles in neuronal homeostasis and activity.Howeve r,its expression and stability are strongly modified in response to cellular stresses,in particular upon alte red oxidative conditions during neurodegeneration.Here,we report and discuss the abundant literature that has highlighted its contribution to the pathophysiology of Parkinson's disease,as well as its therapeutic and prognostic potential in this still incurable pathology.
基金supported by the National Key Technology R&D Program“New Drug Innovation”of China[Nos.2019YFC1711000 and 2019YFC1708902]the National Natural Science Foundation of China[Nos.81973505 and 81773932]
文摘Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells.Mitochondrial dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton proteins.Thus,targeting myosin eactin molecular motor is considered as a promising strategy for anti-cancer.In this study,we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics via pharmacologically targeting molecular motor.Here,we found J13 could directly target myosin-9(MYH9)eactin molecular motor to promote mitochondrial fission progression,and markedly inhibited cancer cells survival,proliferation and migration.Mechanism study revealed that J13 impaired MYH9 eactin interaction to inactivate molecular motor,and caused a cytoskeleton-dependent mitochondrial dynamics imbalance.Moreover,stable isotope labeling with amino acids in cell culture(SILAC)technology-coupled with pulldown analysis identified HSPA9 as a crucial adaptor protein connecting MYH9 eactin molecular motor to mitochondrial fission.Taken together,we reported the first natural small-molecule directly targeting MYH9 eactin molecular motor for anti-cancer translational research.Besides,our study also proved the conceptual practicability of pharmacologically disrupting mitochondrial fission/fusion dynamics in human cancer therapy.
