Simulated microgravity(SMG)poses substantial challenges to astronaut health,particularly impacting osteoblast function and leading to disuse osteoporosis.This study investigates the adverse effects of SMG on osteoblas...Simulated microgravity(SMG)poses substantial challenges to astronaut health,particularly impacting osteoblast function and leading to disuse osteoporosis.This study investigates the adverse effects of SMG on osteoblasts,focusing on changes in mitochondrial dynamics and their consequent effects on cellular energy metabolism and mechanotransduction pathways.We discovered that SMG markedly reduced the expression of osteoblast differentiation markers and promoted mitochondrial fission,as indicated by an increase in punctate mitochondria,a decrease in mitochondrial length,and a reduction in cristae density.These mitochondrial alterations are linked to elevated reactive oxygen species levels,a decrease in ΔΨm,and a metabolic shift from oxidative phosphorylation to glycolysis,resulting in decreased adenosine triphosphate production,which are all indicative of mitochondrial dysfunction.Our results showed that treatment with mitochondrial division inhibitor-1(mdivi-1),a mitochondrial fission inhibitor,effectively inhibited these SMG-induced effects,thereby maintaining mitochondrial structure and function and promoting osteoblast differentiation.Furthermore,SMG disrupted critical mechanotransduction processes,by affecting paxillin expression,the RhoA-ROCK-Myosin Ⅱ pathway,and actin dynamics,which subsequently altered nuclear morphology and disrupted Yes-associated protein signaling.Notably,treatment with mdivi-1 prevented these disruptions in mechanotransduction pathways.Moreover,our study showed that SMG-induced chromatin remodeling and histone methylation,which are epigenetic barriers to osteogenic differentiation,can be reversed by targeting mitochondrial fission,further highlighting the significance of mitochondrial dynamics in osteoblast function in an SMG environment.Therefore,targeting mitochondrial fission emerges as a promising therapeutic strategy to alleviate osteoblast dysfunction under SMG conditions,providing novel approaches to maintain bone health during prolonged space missions and safeguard the astronaut well-being.展开更多
基金supported by the National Natural Science Foundation of China(grant numbers 32171310,12472315,11972067,U20A20390,and 12332019)the Beijing Natural Science Foundation(grant numbers L234072,L242125,and L242042)+1 种基金the State Key Laboratory of Oral Diseases Open Fund(SKLOD2024OF01)the Fundamental Research Funds for the Central Universities.
文摘Simulated microgravity(SMG)poses substantial challenges to astronaut health,particularly impacting osteoblast function and leading to disuse osteoporosis.This study investigates the adverse effects of SMG on osteoblasts,focusing on changes in mitochondrial dynamics and their consequent effects on cellular energy metabolism and mechanotransduction pathways.We discovered that SMG markedly reduced the expression of osteoblast differentiation markers and promoted mitochondrial fission,as indicated by an increase in punctate mitochondria,a decrease in mitochondrial length,and a reduction in cristae density.These mitochondrial alterations are linked to elevated reactive oxygen species levels,a decrease in ΔΨm,and a metabolic shift from oxidative phosphorylation to glycolysis,resulting in decreased adenosine triphosphate production,which are all indicative of mitochondrial dysfunction.Our results showed that treatment with mitochondrial division inhibitor-1(mdivi-1),a mitochondrial fission inhibitor,effectively inhibited these SMG-induced effects,thereby maintaining mitochondrial structure and function and promoting osteoblast differentiation.Furthermore,SMG disrupted critical mechanotransduction processes,by affecting paxillin expression,the RhoA-ROCK-Myosin Ⅱ pathway,and actin dynamics,which subsequently altered nuclear morphology and disrupted Yes-associated protein signaling.Notably,treatment with mdivi-1 prevented these disruptions in mechanotransduction pathways.Moreover,our study showed that SMG-induced chromatin remodeling and histone methylation,which are epigenetic barriers to osteogenic differentiation,can be reversed by targeting mitochondrial fission,further highlighting the significance of mitochondrial dynamics in osteoblast function in an SMG environment.Therefore,targeting mitochondrial fission emerges as a promising therapeutic strategy to alleviate osteoblast dysfunction under SMG conditions,providing novel approaches to maintain bone health during prolonged space missions and safeguard the astronaut well-being.
