AIM: To investigate mitochondrial factors associated with Leber hereditary optic neuropathy (LHON) through complete sequencing and analysis of the mitochondrial genome of Chinese patients with this disease. METHODS: T...AIM: To investigate mitochondrial factors associated with Leber hereditary optic neuropathy (LHON) through complete sequencing and analysis of the mitochondrial genome of Chinese patients with this disease. METHODS: Two unrelated southern Chinese families with LHON and 10 matched healthy controls were recruited, and their entire mitochondrial DNA (mtDNA) was amplified and sequenced with the universal M13 primer. Then DNA sequence analysis and variation identification were performed by DNAssist and Chromas 2 software and compared with authoritative databases such as Mitomap. RESULTS: Mutational analysis of mtDNA in these two Chinese pedigrees revealed one common LHON-associated mutation, G11778A (Arg -> His), in the MT-ND4 gene. In addition, there were two secondary mutations in Pedigree 1: C34971 (Ala -> Val), and C3571T (Leu -> Phe) in the MT-ND1 gene, which have not been reported; and two secondary mutations occurred in Pedigree 2: A10398G (Thr -> Ala) in the MT-ND3 gene, and T14502C (Ile -> Val) in the MT-ND6 gene. Three polymorphisms, A73G, G94A and A263G in the mtDNA control region, were also found. CONCLUSION: Our study confirmed that the known MT-ND4* G11778A mutation is the most significant cause of LHON. The C3497T and C3571T mutations in Pedigree 1 were also both at hot-spots of MT-ND1; they may affect the respiratory chain in coordination with the primary mutation G11778A. In Pedigree 2, the two secondary mutations A10398G of MT-ND3 and T14502C of MT-ND6 may influence mitochondrial respiratory complex I, leading to the mitochondrial respiratory chain dysfunction which results in optic atrophy together with G11778A. Therefore, not only the common primary LHON mutation is responsible for the visual atrophy, but other secondary mtDNA mutations should also be considered when giving genetic counseling.展开更多
Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial function.The roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplor...Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial function.The roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplored in this context.Herein,a previously unknown lncRNA,Gm20257,was identified.It markedly increased under hypertrophic stress in vivo and in vitro.The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy.Conversely,the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensinⅡ-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively,thus restoring cardiac function.Importantly,Gm20257 restored mitochondrial complexⅣlevel and enhanced mitochondrial function.Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1(PGC-1α),which could increase mitochondrial complex IV.Subsequently,Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α.Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1αwas a direct downstream target of Gm20257.This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP.These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complexⅣaxis,offering a novel approach for attenuating pathological cardiac hypertrophy.展开更多
Organelle-targeted imaging can provide information on cellular functions and intracellular interactions,being significant for disease diagnosis.The use of room-temperature phosphorescence(RTP)in organelle-targeted ima...Organelle-targeted imaging can provide information on cellular functions and intracellular interactions,being significant for disease diagnosis.The use of room-temperature phosphorescence(RTP)in organelle-targeted imaging can fully utilize its unique characteristics of long wavelength and deep penetration.However,this technology has long been plagued by insufficient probe targeting and limited luminous intensity.In this work,we prepared a series of complexes composed of multicationic persulfurated arenes and biomacromolecules via electrostatic interactions in 1:1 stoichiometry for high-contrast mitochondrial-targeted RTP imaging.Such an electrostatic interaction design effectively prevented the self-aggregation of the probes,which is not conducive to mitochondrial targeting.Simultaneously,it suppressed the non-radiative decay to the maximum extent,enabling the probes to exhibit strong RTP signals both in aqueous solution and at the cellular level.Furthermore,the biomacromolecules can serve as carriers for an electrostatic interaction transfer of the persulfurated arenes to mitochondria.This leads to high mitochondrial targeting Pearson's correlation coefficients of the probes and high-contrast RTP imaging effects,as well as the independence of the co-incubated probe concentration.These results provide new insights for the development of targeted imaging technologies.展开更多
Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A vari...Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A variation within TRMT2B(c.1356G>T;p.K452N)was identified to be associated with ALS in a family comprising two patients with juvenile ALS(JALS).Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS,and three more variants were identified in a public ALS database including 3317 patients with ALS.A decreased number of mitochondria,swollen mitochondria,lower expression of ND1,decreased mitochondrial complex I activities,lower mitochondrial aerobic respiration,and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells.Further,TRMT2B variations overexpression cells also displayed decreased ND1.In conclusion,a novel JALS-associated gene called TRMT2B was identified,thus broadening the clinical and genetic spectrum of ALS.展开更多
Sulfonylureas are widely used oral anti-diabetic drugs.However,its long-term usage effects on patients’lifespan remain controversial,with no reports of influence on animal longevity.Hence,the anti-aging effects of ch...Sulfonylureas are widely used oral anti-diabetic drugs.However,its long-term usage effects on patients’lifespan remain controversial,with no reports of influence on animal longevity.Hence,the anti-aging effects of chlorpropamide along with glimepiride,glibenclamide,and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+(mito K-ATP)channels and mitochondrial complex II.Chlorpropamide delayed aging in Caenorhabditis elegans,human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice.In addition,the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms,which is consistent with the function of its reported targets,mito K-ATP channels.Increased levels of mitochondrial reactive oxygen species(mt ROS)were observed in chlorpropamide-treated worms.Moreover,the lifespan extension by chlorpropamide required complex II and increased mt ROS levels,indicating that chlorpropamide acts on complex II directly or indirectly via mito K-ATP to increase the production of mt ROS as a pro-longevity signal.This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C.elegans.展开更多
MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a pr...MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.展开更多
Objective We previously reported that mutations in inner mitochondrial membrane peptidase 2-like(Immp2l)increase infarct volume,enhance superoxide production,and suppress mitochondrial respiration after transient cere...Objective We previously reported that mutations in inner mitochondrial membrane peptidase 2-like(Immp2l)increase infarct volume,enhance superoxide production,and suppress mitochondrial respiration after transient cerebral focal ischemia and reperfusion injury.The present study investigated the impact of heterozygous Immp2l mutation on mitochondria function after ischemia and reperfusion injury in mice.Methods Mice were subjected to middle cerebral artery occlusion for 1 h followed by 0,1,5,and 24 h of reperfusion.The effects of Immp2l^(+/−)on mitochondrial membrane potential,mitochondrial respiratory complex III activity,caspase-3,and apoptosis-inducing factor(AIF)translocation were examined.Results Immp2l^(+/−)increased ischemic brain damage and the number of TUNEL-positive cells compared with wild-type mice.Immp2l^(+/−)led to mitochondrial damage,mitochondrial membrane potential depolarization,mitochondrial respiratory complex III activity suppression,caspase-3 activation,and AIF nuclear translocation.Conclusion The adverse impact of Immp2l^(+/−)on the brain after ischemia and reperfusion might be related to mitochondrial damage that involves depolarization of the mitochondrial membrane potential,inhibition of the mitochondrial respiratory complex III,and activation of mitochondria-mediated cell death pathways.These results suggest that patients with stroke carrying Immp2l^(+/−)might have worse and more severe infarcts,followed by a worse prognosis than those without Immp2l mutations.展开更多
The mitochondrial respiratory complex Ⅱ or succinate:ubiquinone oxidoreductase(SQR)is a key membrane complex in both the tricarboxylic acid cycle and aerobic respiration.Five disinfectant compounds were investigated ...The mitochondrial respiratory complex Ⅱ or succinate:ubiquinone oxidoreductase(SQR)is a key membrane complex in both the tricarboxylic acid cycle and aerobic respiration.Five disinfectant compounds were investigated with their potent inhibition effects on the ubiquinone reduction activity of the porcine mitochondrial SQR by enzymatic assay and crystallography.Crystal structure of the SQR bound with thiabendazole(TBZ)reveals a different inhibitor-binding feature at the ubiquinone binding site where a water molecule plays an important role.The obvious inhibitory effect of TBZ based on the biochemical data(IC50~100μmol/L)and the significant structure-based binding affinity calculation(~94μmol/L)draw the suspicion of using TBZ as a good disinfectant compound for nematode infections treatment and fruit storage.展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disease,which is characterized by loss of dopaminergic(DA)neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neu...Parkinson’s disease(PD)is the second most common neurodegenerative disease,which is characterized by loss of dopaminergic(DA)neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases.Although the cause of PD is still unclear,the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis.Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss.Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis.The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD.Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin-or genetic factorinduced PD cellular and animal models.Moreover,PINK1 and parkin,two autosomal recessive PD gene products,have important roles in mitophagy,a cellular process to clear damaged mitochondria.PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy.In this review,we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD.展开更多
Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes.A nuclear gene HPDL(4-hydroxyphenylpyruvate dioxygenase-like),which encodes an intermembrane mitochondrial protein,has been recen...Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes.A nuclear gene HPDL(4-hydroxyphenylpyruvate dioxygenase-like),which encodes an intermembrane mitochondrial protein,has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes.Here,we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity,including developmental delay/intellectual disability,spasm,and hypertonia.Seven different pathogenic variants are identified,of which five are novel.Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function,which is also observed in HPDL-knockdown(KD)He La cells.In these He La cells,overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate.In addition,a decreased activity of the oxidative phosphorylation(OXPHOS)complex II is observed in patient-derived lymphocytes and HPDL-KD He La cells,further supporting an essential role of HPDL in the mitochondrial respiratory chain.Collectively,our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.展开更多
基金Supported by the National Natural Science Foundation of China(No.J0710043)
文摘AIM: To investigate mitochondrial factors associated with Leber hereditary optic neuropathy (LHON) through complete sequencing and analysis of the mitochondrial genome of Chinese patients with this disease. METHODS: Two unrelated southern Chinese families with LHON and 10 matched healthy controls were recruited, and their entire mitochondrial DNA (mtDNA) was amplified and sequenced with the universal M13 primer. Then DNA sequence analysis and variation identification were performed by DNAssist and Chromas 2 software and compared with authoritative databases such as Mitomap. RESULTS: Mutational analysis of mtDNA in these two Chinese pedigrees revealed one common LHON-associated mutation, G11778A (Arg -> His), in the MT-ND4 gene. In addition, there were two secondary mutations in Pedigree 1: C34971 (Ala -> Val), and C3571T (Leu -> Phe) in the MT-ND1 gene, which have not been reported; and two secondary mutations occurred in Pedigree 2: A10398G (Thr -> Ala) in the MT-ND3 gene, and T14502C (Ile -> Val) in the MT-ND6 gene. Three polymorphisms, A73G, G94A and A263G in the mtDNA control region, were also found. CONCLUSION: Our study confirmed that the known MT-ND4* G11778A mutation is the most significant cause of LHON. The C3497T and C3571T mutations in Pedigree 1 were also both at hot-spots of MT-ND1; they may affect the respiratory chain in coordination with the primary mutation G11778A. In Pedigree 2, the two secondary mutations A10398G of MT-ND3 and T14502C of MT-ND6 may influence mitochondrial respiratory complex I, leading to the mitochondrial respiratory chain dysfunction which results in optic atrophy together with G11778A. Therefore, not only the common primary LHON mutation is responsible for the visual atrophy, but other secondary mtDNA mutations should also be considered when giving genetic counseling.
基金supported by the National Natural Science Foundation of China(Nos.82170299 and 82003757)Major Projects of the National Natural Science Foundation of China(No.82330011)+1 种基金the National Natural Science Foundation of China(No.82370279)the Postdoctoral Starting Fund of Heilongjiang Province(No.LBH-Q21121).
文摘Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial function.The roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplored in this context.Herein,a previously unknown lncRNA,Gm20257,was identified.It markedly increased under hypertrophic stress in vivo and in vitro.The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy.Conversely,the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensinⅡ-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively,thus restoring cardiac function.Importantly,Gm20257 restored mitochondrial complexⅣlevel and enhanced mitochondrial function.Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1(PGC-1α),which could increase mitochondrial complex IV.Subsequently,Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α.Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1αwas a direct downstream target of Gm20257.This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP.These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complexⅣaxis,offering a novel approach for attenuating pathological cardiac hypertrophy.
基金supported by the National Natural Science Foundation of China(22275038)partially funded by the Swedish Research Council(2022-06725)+1 种基金the support from the Swedish Research Council(2020-04600)funded by the European Union(ERC,LUMOR,101077649)the support from the Swedish Science Research Council(2022-03405)。
文摘Organelle-targeted imaging can provide information on cellular functions and intracellular interactions,being significant for disease diagnosis.The use of room-temperature phosphorescence(RTP)in organelle-targeted imaging can fully utilize its unique characteristics of long wavelength and deep penetration.However,this technology has long been plagued by insufficient probe targeting and limited luminous intensity.In this work,we prepared a series of complexes composed of multicationic persulfurated arenes and biomacromolecules via electrostatic interactions in 1:1 stoichiometry for high-contrast mitochondrial-targeted RTP imaging.Such an electrostatic interaction design effectively prevented the self-aggregation of the probes,which is not conducive to mitochondrial targeting.Simultaneously,it suppressed the non-radiative decay to the maximum extent,enabling the probes to exhibit strong RTP signals both in aqueous solution and at the cellular level.Furthermore,the biomacromolecules can serve as carriers for an electrostatic interaction transfer of the persulfurated arenes to mitochondria.This leads to high mitochondrial targeting Pearson's correlation coefficients of the probes and high-contrast RTP imaging effects,as well as the independence of the co-incubated probe concentration.These results provide new insights for the development of targeted imaging technologies.
基金supported by the Program of the National Natural Science Foundation of China(Nos.82171431 and 31972886)the Natural Science Fund for Distinguished Young Scholars of Hunan Province,China(Nos.2020JJ2057 and 2021JJ10074)+6 种基金Natural Science Foundation of Changsha City(No.kq2208402)the Program of the National Natural Science Foundation of Hunan Province(No.2021JJ40989)the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital(No.2020LNJJ13)the Science and Technology Innovation 2030(STI2030-Major Projects,No.2021ZD0201803)the National Key R&D Program of China(No.2021YFA0805202)the Innovation Team Project of Hunan Province(No.2019RS1010)the Innovation Team Project of Central South University(No.2020CX016).
文摘Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A variation within TRMT2B(c.1356G>T;p.K452N)was identified to be associated with ALS in a family comprising two patients with juvenile ALS(JALS).Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS,and three more variants were identified in a public ALS database including 3317 patients with ALS.A decreased number of mitochondria,swollen mitochondria,lower expression of ND1,decreased mitochondrial complex I activities,lower mitochondrial aerobic respiration,and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells.Further,TRMT2B variations overexpression cells also displayed decreased ND1.In conclusion,a novel JALS-associated gene called TRMT2B was identified,thus broadening the clinical and genetic spectrum of ALS.
基金Financial support for this research provided by the National Natural Science Foundation of China(22037002 and 81772689)the Program for Professor of Special Appointment(Eastern Scholar TP2018025,China)at Shanghai Institutions of Higher Learning+2 种基金the Innovative Research Team of High-level Local Universities in Shanghaithe Chinese Special Fund for State Key Laboratory of Bioreactor Engineering(2060204,China)Strains of Caenorhabditis elegans were provided by the CGC,which is funded by NIH Office of Research Infrastructure Programs(P40 OD010440)。
文摘Sulfonylureas are widely used oral anti-diabetic drugs.However,its long-term usage effects on patients’lifespan remain controversial,with no reports of influence on animal longevity.Hence,the anti-aging effects of chlorpropamide along with glimepiride,glibenclamide,and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+(mito K-ATP)channels and mitochondrial complex II.Chlorpropamide delayed aging in Caenorhabditis elegans,human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice.In addition,the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms,which is consistent with the function of its reported targets,mito K-ATP channels.Increased levels of mitochondrial reactive oxygen species(mt ROS)were observed in chlorpropamide-treated worms.Moreover,the lifespan extension by chlorpropamide required complex II and increased mt ROS levels,indicating that chlorpropamide acts on complex II directly or indirectly via mito K-ATP to increase the production of mt ROS as a pro-longevity signal.This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C.elegans.
基金sponsored by the National Natural Science Foundation of China(82122045,82073073,81874207,and 81872418)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210802,China)+4 种基金MOE Key Laboratory of Biosystems Homeostasis&Protection(Zhejiang University,China)Science and Technology Commission of Shanghai Municipality(21S11902000,China)Jointed PI Program from Shanghai Changning Maternity and Infant Health Hospital(11300-412311-20033,China)ECNU Construction Fund of Innovation and Entrepreneurship Laboratory(44400-20201-532300/021,China)the ECNU multifunctional platform for innovation(011 and 004,China).
文摘MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.
基金This study was supported by the National Natural Science Foundation of China(Nos.81360196,81760240the Natural Science Foundation of Ningxia(No.2022AAC03159)the Ningxia Innovation Team of the Foundation and Clinical Research of Diabetes and Its Complications(No.NXKJT2019010).
文摘Objective We previously reported that mutations in inner mitochondrial membrane peptidase 2-like(Immp2l)increase infarct volume,enhance superoxide production,and suppress mitochondrial respiration after transient cerebral focal ischemia and reperfusion injury.The present study investigated the impact of heterozygous Immp2l mutation on mitochondria function after ischemia and reperfusion injury in mice.Methods Mice were subjected to middle cerebral artery occlusion for 1 h followed by 0,1,5,and 24 h of reperfusion.The effects of Immp2l^(+/−)on mitochondrial membrane potential,mitochondrial respiratory complex III activity,caspase-3,and apoptosis-inducing factor(AIF)translocation were examined.Results Immp2l^(+/−)increased ischemic brain damage and the number of TUNEL-positive cells compared with wild-type mice.Immp2l^(+/−)led to mitochondrial damage,mitochondrial membrane potential depolarization,mitochondrial respiratory complex III activity suppression,caspase-3 activation,and AIF nuclear translocation.Conclusion The adverse impact of Immp2l^(+/−)on the brain after ischemia and reperfusion might be related to mitochondrial damage that involves depolarization of the mitochondrial membrane potential,inhibition of the mitochondrial respiratory complex III,and activation of mitochondria-mediated cell death pathways.These results suggest that patients with stroke carrying Immp2l^(+/−)might have worse and more severe infarcts,followed by a worse prognosis than those without Immp2l mutations.
基金supported by grants from the National Basic Research Program(973 Program)(Nos.2011CB910301,2011CB910900,and 2006CB806506)the National Natural Science Foundation of China(Grant No.31021062).
文摘The mitochondrial respiratory complex Ⅱ or succinate:ubiquinone oxidoreductase(SQR)is a key membrane complex in both the tricarboxylic acid cycle and aerobic respiration.Five disinfectant compounds were investigated with their potent inhibition effects on the ubiquinone reduction activity of the porcine mitochondrial SQR by enzymatic assay and crystallography.Crystal structure of the SQR bound with thiabendazole(TBZ)reveals a different inhibitor-binding feature at the ubiquinone binding site where a water molecule plays an important role.The obvious inhibitory effect of TBZ based on the biochemical data(IC50~100μmol/L)and the significant structure-based binding affinity calculation(~94μmol/L)draw the suspicion of using TBZ as a good disinfectant compound for nematode infections treatment and fruit storage.
基金This work was supported by the National Basic Research Program of China(2012CB947602)the National Natural Sciences Foundation of China(No.31300887)+2 种基金Natural Science Foundation of Jiangsu Province(BK20130299)Suzhou Clinical Research Center of Neurological Disease(Szzx201503)Jiangsu Provincial Special Program of Medical Science(BL2014042).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disease,which is characterized by loss of dopaminergic(DA)neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases.Although the cause of PD is still unclear,the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis.Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss.Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis.The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD.Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin-or genetic factorinduced PD cellular and animal models.Moreover,PINK1 and parkin,two autosomal recessive PD gene products,have important roles in mitophagy,a cellular process to clear damaged mitochondria.PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy.In this review,we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD.
基金funded by the Precision Medical Research of National Key Research and Development Program(2018YFC1002200,2019YFC1005100 to Y.Yu,2018YFC1002400 to Y.Sun,and 2018YFC1002501 to Y.Shen)National Natural Science Foundation of China(81873633 and 82071276 to Y.Shen,81830071 to J.Lyu,81873724 to Y.Sun,and 82070914 and 81873671 to Y.Yu)+7 种基金Shanghai Shen Kang Hospital Development Center(SHDC12017109 to Y.Yu)the Shanghai Science and Technology Commission(19140904500 to Y.Yu)Jiaotong University Cross Biomedical Engineering(YG2017MS72 to Y.Yu)the“Eastern Scholar”Fundthe“Guangxi Bagui Scholar”fund(to Y.Shen)the Major Research Plan of the Provincial Science and Technology Foundation of Guangxi(AB16380214 to Y.Shen)Foundation of Shanghai Municipal Health Commission(shslczdzk05702,to Y.Yu and Y.Sun)Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20191908,to Y.Yu)。
文摘Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes.A nuclear gene HPDL(4-hydroxyphenylpyruvate dioxygenase-like),which encodes an intermembrane mitochondrial protein,has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes.Here,we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity,including developmental delay/intellectual disability,spasm,and hypertonia.Seven different pathogenic variants are identified,of which five are novel.Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function,which is also observed in HPDL-knockdown(KD)He La cells.In these He La cells,overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate.In addition,a decreased activity of the oxidative phosphorylation(OXPHOS)complex II is observed in patient-derived lymphocytes and HPDL-KD He La cells,further supporting an essential role of HPDL in the mitochondrial respiratory chain.Collectively,our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.
