Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer’s disease(AD).The mitochondrial contact site and cristae organizing system(MICOS)plays a pivotal role in shaping the inner mitochondrial...Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer’s disease(AD).The mitochondrial contact site and cristae organizing system(MICOS)plays a pivotal role in shaping the inner mitochondrial membrane,forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function.In the past decade,MICOS abnormalities have been extensively linked to AD pathogenesis.In particular,dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD,often in association with hallmark pathological features such as amyloid-b plaque accumulation,neurofibrillary tangle formation,and neuronal apoptosis.Furthermore,MICOS subunits interact with several etiologically relevant proteins,significantly influencing AD progression.The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD.Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment.In the present review,we introduce current understanding of MICOS structures and functions,highlight MICOS pathogenesis in AD,and summarize the available MICOS-targeting drugs potentially useful for AD.展开更多
Background:Parkinson’s disease(PD)is the second most common neurodegenerative disease after Alzheimer’s dementia.Mitochondrial dysfunction is involved in the pathology of PD.Coiled-coil-helix-coiled-coil-helix domai...Background:Parkinson’s disease(PD)is the second most common neurodegenerative disease after Alzheimer’s dementia.Mitochondrial dysfunction is involved in the pathology of PD.Coiled-coil-helix-coiled-coil-helix domain-containing 2(CHCHD2)was identified as associated with autosomal dominant PD.However,the mechanism of CHCHD2 in PD remains unclear.Methods:Short hairpin RNA(ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma(SHSY5Y)and HeLa cells.Blue-native polyacrylamide gel electrophoresis(PAGE)and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system(MICOS).Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10.Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)administration were used to examine the influence of CHCHD2 in vivo.Results:We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium(MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model.Furthermore,we identified that CHCHD2 interacted with Mic10,and overexpression of CHCHD2 can protect against MPP+-induced MICOS impairment,while knockdown of CHCHD2 impaired the stability of MICOS.Conclusion:This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex,which contributes to protecting mitochondrial function in PD.展开更多
基金funded by the National Natural Science Foundation of China(No.81500858 to Xinwen Zhang,No.81700977 to Xu Yan)Natural Science Foundation of Liaoning Province(China)(No.2022-MS-231 to Xinwen Zhang)+1 种基金the Science and Technology Planning Project of Shenyang(China)(No.22-321-33-26 to Dehao Shang)Grants-in-Aid for Scientific Research(Japan)(No.22K09927 to Zhou Wu).
文摘Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer’s disease(AD).The mitochondrial contact site and cristae organizing system(MICOS)plays a pivotal role in shaping the inner mitochondrial membrane,forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function.In the past decade,MICOS abnormalities have been extensively linked to AD pathogenesis.In particular,dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD,often in association with hallmark pathological features such as amyloid-b plaque accumulation,neurofibrillary tangle formation,and neuronal apoptosis.Furthermore,MICOS subunits interact with several etiologically relevant proteins,significantly influencing AD progression.The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD.Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment.In the present review,we introduce current understanding of MICOS structures and functions,highlight MICOS pathogenesis in AD,and summarize the available MICOS-targeting drugs potentially useful for AD.
基金supported by research grants from the National Natural Science Foundation of China(Nos.81901282,81870992,82071444)the Nature Science Foundation of Guangdong Province(Nos.2019A1515011189,2020A1515010985)the Technology Project of Guangzhou(Nos.202102020029,2019ZD09).
文摘Background:Parkinson’s disease(PD)is the second most common neurodegenerative disease after Alzheimer’s dementia.Mitochondrial dysfunction is involved in the pathology of PD.Coiled-coil-helix-coiled-coil-helix domain-containing 2(CHCHD2)was identified as associated with autosomal dominant PD.However,the mechanism of CHCHD2 in PD remains unclear.Methods:Short hairpin RNA(ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma(SHSY5Y)and HeLa cells.Blue-native polyacrylamide gel electrophoresis(PAGE)and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system(MICOS).Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10.Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)administration were used to examine the influence of CHCHD2 in vivo.Results:We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium(MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model.Furthermore,we identified that CHCHD2 interacted with Mic10,and overexpression of CHCHD2 can protect against MPP+-induced MICOS impairment,while knockdown of CHCHD2 impaired the stability of MICOS.Conclusion:This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex,which contributes to protecting mitochondrial function in PD.
