Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondr...Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondrial respiratory complexes and metabolites,in controlling myeloid immune responses,is well-documented but not fully understood in diseases of the central nervous system (CNS).The groundbreaking study by Prof.Peruzzotti-Jametti et al.[1],entitled"Mitochondrial complexⅠactivity in microglia sustains neuroinflammation"published in Nature,delves into the intricate dynamics between mitochondrial function within microglia and the perpetuation of chronic neuroinflammation,specifically in MS.The core point of their investigation is the hypothesis that mitochondrial complexⅠ(CI) activity,through a mechanism known as reverse electron transport (RET),generates reactive oxygen species (ROS) in microglia,thereby sustaining inflammatory response in the CNS.This increases ROS production from the mitochondria,which is thought to be a crucial factor in the maintenance of a pro-inflammatory state in the microglia,contributing to the pathology of MS and similar neuroinflammatory diseases.展开更多
Host expansion facilitates tephritid flies to expand their ranges.Unraveling the mechanisms of host expansion will help to efficiently control these pests.Our previous works showed mitochondrial complex I genes Ndufs1...Host expansion facilitates tephritid flies to expand their ranges.Unraveling the mechanisms of host expansion will help to efficiently control these pests.Our previous works showed mitochondrial complex I genes Ndufs1,Ndufs3,and Ndufa7 being upregulated during host expansion of Bactrocera tau(Walker),one of the highly hazardous species of tephritids.However,their roles in the host expansion of B.tau remain unknown.Here,using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease 9(Cas9)editing system for the first time,a stable homozygous Ndufa7 strain(Btndufa7^(-/-)),heterozygous Ndufs1(Btndufs1^(+/-)),and Ndufs3 strains(Btndufs3^(+/-))were obtained from F3 generation of B.tau,after gene knockout.Reduced sizes of larvae and pupae of the Ndufa7 knockout strain were first observed.Notably,the mean values of fitness estimation(pupal numbers,single-pupal weight and emergence rate)and Ndufa7 gene expression in the Ndufa7 knockout strain were slightly reduced on 2 native hosts(summer squash and cucumber),while it sharply decreased on the novel host banana and the potential host pitaya,compared with those of the wild-type strain.Furthermore,the Ndufa7 knockout strain did not survive on the novel host guava.These results suggested that Ndufa7 disturbs the survival on native hosts,expansion to novel hosts,and further expansion to potential hosts of B.tau.Homozygous lethality occurred after the knockout of Ndufs1 or Ndufs3,suggesting that these 2 genes play a role in the early development of B.tau.This study revealed that Ndufa7 is a target gene for the management of tephritids and opens a new avenue for pest control research.展开更多
Background Epidemiological studies have revealed increased Parkinson’s disease(PD)risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).MPTP is frequently used to induce...Background Epidemiological studies have revealed increased Parkinson’s disease(PD)risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).MPTP is frequently used to induce PD-like symptoms in research models by disrupting mitochondrial complex I(CI)function and causing dopaminergic neuronal loss in the nigrostriatal region.However,the pathway(s)through which MPTP impairs mitochondrial CI function remain to be elucidated.In this study,we aim to identify the molecular mechanisms through which MPTP modulates CI function and define the specific subunits of mitochondrial CI affected by MPTP.Methods Male mice encompassing either wild-type Sirt3 or Sirt3 K223R de-SUMOylation mutation,were intraperitoneally injected with either MPTP or saline.In vitro experiments were conducted using the SH-SY5Y cell line with or without the Sirt3 de-SUMOylation mutation.Movement performance,mitochondrial function,and protein acetylation were evaluated.Results MPTP exposure,both in vitro and in vivo,disrupted the AMPK–SENP1–Sirt3 axis,leading to impairment of mitochondrial function.Specifically,MPTP suppressed activation of AMPK,impeding the entry of SENP1 into the mitochondria.The lack of mitochondrial SENP1 resulted in increased levels of SUMOylated Sirt3,which inhibited its deacetylase activity.This led to a significant increase in the acetylation of CI subunits NDUFS3 and NDUFA5,which resulted in reduced CI activity and inhibition of mitochondrial function,and eventually dopaminergic neuronal death.In this pathway,sustained deSUMOylation mutation of Sirt3(K223R in mice,K288R in humans)mitigated the impact of MPTP on mitochondrial dysregulation,as well as dopaminergic neuronal death and behavioral deficits.Conclusion The disordered AMPK-SENP1-Sirt3 pathway plays a crucial role in the MPTP-induced CI dysfunction and PD-like phenotype,which provide valuable insights into the mechanisms of PD pathogenesis.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
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
The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are...The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are characterized by increased levels of mitochondrial complexesⅠ,Ⅱ,and Ⅳ followed by increased superoxide anion generation.Moreover,As（V） triggers an apoptotic mode of cell death,demonstrated by an apoptotic SubG1 peak,associated with an alteration of plasma membrane integrity.There is also a decrease in transmembrane mitochondrial potential and mitochondrial adenosine triphosphate ATP.It is therefore tempting to speculate that As（V） triggers mitochondrial dysfunction,which may lead to defective oxidative phosphorylation subsequently causing mitochondrial oxidative damage,which in turn induces an apoptotic mode of cell death.展开更多
Many metabolic diseases show mitochondrial abnormalities because of dysfunction of complexⅠ(CI).Therefore,the discovery of drugs that target the CI is of great interest.Berberine(BBR)is a botanic agent and has been i...Many metabolic diseases show mitochondrial abnormalities because of dysfunction of complexⅠ(CI).Therefore,the discovery of drugs that target the CI is of great interest.Berberine(BBR)is a botanic agent and has been included in the latest ESC/EAS Guidelines for the management of dyslipidemias.Here,we showed that BBR enters hepatocyte mitochondria after oral administration and improves glucose and lipid metabolism by reducing oxidative phosphorylation in hepatocytes.BBR inhibits CI function rapidly,selectively,and reversibly,not by directly inhibiting CI enzyme activity but by reducing the abundance of CI in the mitochondria through dissociation of CI.BBR directly binds to and activates Sirtuin 3(SIRT3),thereby reducing acetylation of the catalytic subunit NDUFS1 in the N-module of CI,leading to dissociation of mitochondrial CI.Conclusively,BBR,as a mitochondria-homing agent,selectively and reversibly dissociates mitochondrial CI through SIRT3-dependent NDUFS1 deacetylation to improve hepatocellular glucose and lipid metabolism,highlighting that CI may be a promising target for innovative natural products to treat metabolic diseases.展开更多
Mitochondrial respiratory complexes(Complexes I–V)and their assembly into respiratory supercomplexes(SCs)are fundamental to liver bioenergetics,redox homeostasis,and metabolic adaptability.Disruption of these systems...Mitochondrial respiratory complexes(Complexes I–V)and their assembly into respiratory supercomplexes(SCs)are fundamental to liver bioenergetics,redox homeostasis,and metabolic adaptability.Disruption of these systems contributes to major liver diseases,including non-alcoholic fatty liver disease,alcoholic liver disease,drug-induced liver injury,viral hepatitis,and hepatocellular carcinoma,by impairing adenosine triphosphate synthesis,increasing oxidative stress,and altering metabolic pathways.Recent advances have clarified the structural-functional interdependence of individual complexes within SCs,revealing their dynamic remodeling in response to physiological stress and pathological injury.These insights open opportunities for clinical translation,such as targeting SC stability with pharmacological agents,nutritional strategies,or gene therapy,and employing mitochondrial transplantation in cases of severe mitochondrial failure.Precision medicine approaches,incorporating multi-omics profiling and patient-derived models,may enable individualized interventions and early detection using SC integrity as a biomarker.By linking molecular mechanisms to therapeutic strategies,this review underscores the potential of mitochondrial-targeted interventions to improve outcomes in patients with liver disease.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
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
Mitochondria are cellular organelles that originate from an endosymbiotic bacterial ancestor and are primarily responsible for ATP generation via oxidative phosphorylation(OXPHOS).OXPHOS is conducted by five mitochond...Mitochondria are cellular organelles that originate from an endosymbiotic bacterial ancestor and are primarily responsible for ATP generation via oxidative phosphorylation(OXPHOS).OXPHOS is conducted by five mitochondrial respiratory complexes in the inner mitochondrial membrane.Human mitochondria possess a distinct genome,a small,circular,double-stranded DNA(mtDNA)of 16,569 base pairs.This genome encodes 37 genes.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
Protein complexes are important for almost all biological processes.Hence,to fully understand how cells work,it is also necessary to characterize protein complexes and their dynamics in response to various cellular cu...Protein complexes are important for almost all biological processes.Hence,to fully understand how cells work,it is also necessary to characterize protein complexes and their dynamics in response to various cellular cues.Moreover,the dynamics of protein interaction play crucial roles in regulating the(dis)association of protein complexes and,in turn,regulating biological processes such as metabolism.Here,mitochondrial protein complexes were investigated by blue native PAGE and size-exclusion chromatography under conditions of oxidative stress in order to monitor their dynamic(dis)associations.Rearrangements of enzyme interactions and changes in protein complex abundance were observed in response to oxidative stress induced by menadione treatment.These included changes in enzymatic protein complexes involving g-amino butyric acid transaminase(GABA-T),D-ornithine aminotransferase(D-OAT),or proline dehydrogenase 1(POX1)that are expected to affect proline metabolism.Menadione treatment also affected interactions between several enzymes of the tricarboxylic acid(TCA)cycle and the abundance of complexes of the oxidative phosphorylation pathway.In addition,we compared the mitochondrial complexes of roots and shoots.Considerable differences between the two tissues were observed in the mitochondrial import/export apparatus,the formation of super-complexes in the oxidative phosphorylation pathway,and specific interactions between enzymes of the TCA cycle that we postulate may be related to the metabolic/energetic requirements of roots and shoots.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
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
基金supported by the Taishan Scholars Program of Shandong Province(tsqn202312344).
文摘Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondrial respiratory complexes and metabolites,in controlling myeloid immune responses,is well-documented but not fully understood in diseases of the central nervous system (CNS).The groundbreaking study by Prof.Peruzzotti-Jametti et al.[1],entitled"Mitochondrial complexⅠactivity in microglia sustains neuroinflammation"published in Nature,delves into the intricate dynamics between mitochondrial function within microglia and the perpetuation of chronic neuroinflammation,specifically in MS.The core point of their investigation is the hypothesis that mitochondrial complexⅠ(CI) activity,through a mechanism known as reverse electron transport (RET),generates reactive oxygen species (ROS) in microglia,thereby sustaining inflammatory response in the CNS.This increases ROS production from the mitochondria,which is thought to be a crucial factor in the maintenance of a pro-inflammatory state in the microglia,contributing to the pathology of MS and similar neuroinflammatory diseases.
基金supported by grants from the National Science Foundation of China(32060314,32271563 and 32471568)the Science and Technology Program of Yunnan Province(202401AS070151).
文摘Host expansion facilitates tephritid flies to expand their ranges.Unraveling the mechanisms of host expansion will help to efficiently control these pests.Our previous works showed mitochondrial complex I genes Ndufs1,Ndufs3,and Ndufa7 being upregulated during host expansion of Bactrocera tau(Walker),one of the highly hazardous species of tephritids.However,their roles in the host expansion of B.tau remain unknown.Here,using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease 9(Cas9)editing system for the first time,a stable homozygous Ndufa7 strain(Btndufa7^(-/-)),heterozygous Ndufs1(Btndufs1^(+/-)),and Ndufs3 strains(Btndufs3^(+/-))were obtained from F3 generation of B.tau,after gene knockout.Reduced sizes of larvae and pupae of the Ndufa7 knockout strain were first observed.Notably,the mean values of fitness estimation(pupal numbers,single-pupal weight and emergence rate)and Ndufa7 gene expression in the Ndufa7 knockout strain were slightly reduced on 2 native hosts(summer squash and cucumber),while it sharply decreased on the novel host banana and the potential host pitaya,compared with those of the wild-type strain.Furthermore,the Ndufa7 knockout strain did not survive on the novel host guava.These results suggested that Ndufa7 disturbs the survival on native hosts,expansion to novel hosts,and further expansion to potential hosts of B.tau.Homozygous lethality occurred after the knockout of Ndufs1 or Ndufs3,suggesting that these 2 genes play a role in the early development of B.tau.This study revealed that Ndufa7 is a target gene for the management of tephritids and opens a new avenue for pest control research.
基金supported by National Natural Science Foundation of China(82171427,82101324 and 82471458).
文摘Background Epidemiological studies have revealed increased Parkinson’s disease(PD)risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).MPTP is frequently used to induce PD-like symptoms in research models by disrupting mitochondrial complex I(CI)function and causing dopaminergic neuronal loss in the nigrostriatal region.However,the pathway(s)through which MPTP impairs mitochondrial CI function remain to be elucidated.In this study,we aim to identify the molecular mechanisms through which MPTP modulates CI function and define the specific subunits of mitochondrial CI affected by MPTP.Methods Male mice encompassing either wild-type Sirt3 or Sirt3 K223R de-SUMOylation mutation,were intraperitoneally injected with either MPTP or saline.In vitro experiments were conducted using the SH-SY5Y cell line with or without the Sirt3 de-SUMOylation mutation.Movement performance,mitochondrial function,and protein acetylation were evaluated.Results MPTP exposure,both in vitro and in vivo,disrupted the AMPK–SENP1–Sirt3 axis,leading to impairment of mitochondrial function.Specifically,MPTP suppressed activation of AMPK,impeding the entry of SENP1 into the mitochondria.The lack of mitochondrial SENP1 resulted in increased levels of SUMOylated Sirt3,which inhibited its deacetylase activity.This led to a significant increase in the acetylation of CI subunits NDUFS3 and NDUFA5,which resulted in reduced CI activity and inhibition of mitochondrial function,and eventually dopaminergic neuronal death.In this pathway,sustained deSUMOylation mutation of Sirt3(K223R in mice,K288R in humans)mitigated the impact of MPTP on mitochondrial dysregulation,as well as dopaminergic neuronal death and behavioral deficits.Conclusion The disordered AMPK-SENP1-Sirt3 pathway plays a crucial role in the MPTP-induced CI dysfunction and PD-like phenotype,which provide valuable insights into the mechanisms of PD pathogenesis.
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 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 grants from the University of Bourgogne(Dijon,France)the University of Monastir(Monastir,Tunisia)
文摘The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are characterized by increased levels of mitochondrial complexesⅠ,Ⅱ,and Ⅳ followed by increased superoxide anion generation.Moreover,As（V） triggers an apoptotic mode of cell death,demonstrated by an apoptotic SubG1 peak,associated with an alteration of plasma membrane integrity.There is also a decrease in transmembrane mitochondrial potential and mitochondrial adenosine triphosphate ATP.It is therefore tempting to speculate that As（V） triggers mitochondrial dysfunction,which may lead to defective oxidative phosphorylation subsequently causing mitochondrial oxidative damage,which in turn induces an apoptotic mode of cell death.
基金supported by CAMS Innovation Fund for Medical Sciences(2023-I2M-2-006,2022-I2M-2-002,2021-I2M-1-028)。
文摘Many metabolic diseases show mitochondrial abnormalities because of dysfunction of complexⅠ(CI).Therefore,the discovery of drugs that target the CI is of great interest.Berberine(BBR)is a botanic agent and has been included in the latest ESC/EAS Guidelines for the management of dyslipidemias.Here,we showed that BBR enters hepatocyte mitochondria after oral administration and improves glucose and lipid metabolism by reducing oxidative phosphorylation in hepatocytes.BBR inhibits CI function rapidly,selectively,and reversibly,not by directly inhibiting CI enzyme activity but by reducing the abundance of CI in the mitochondria through dissociation of CI.BBR directly binds to and activates Sirtuin 3(SIRT3),thereby reducing acetylation of the catalytic subunit NDUFS1 in the N-module of CI,leading to dissociation of mitochondrial CI.Conclusively,BBR,as a mitochondria-homing agent,selectively and reversibly dissociates mitochondrial CI through SIRT3-dependent NDUFS1 deacetylation to improve hepatocellular glucose and lipid metabolism,highlighting that CI may be a promising target for innovative natural products to treat metabolic diseases.
基金funded by the Research Project of Zhejiang Chinese Medical University(grant number 2024JKJNTZ01)the Chinese Medicine Science Foundation of Zhejiang Chinese Medical University(grant number 2023J05).
文摘Mitochondrial respiratory complexes(Complexes I–V)and their assembly into respiratory supercomplexes(SCs)are fundamental to liver bioenergetics,redox homeostasis,and metabolic adaptability.Disruption of these systems contributes to major liver diseases,including non-alcoholic fatty liver disease,alcoholic liver disease,drug-induced liver injury,viral hepatitis,and hepatocellular carcinoma,by impairing adenosine triphosphate synthesis,increasing oxidative stress,and altering metabolic pathways.Recent advances have clarified the structural-functional interdependence of individual complexes within SCs,revealing their dynamic remodeling in response to physiological stress and pathological injury.These insights open opportunities for clinical translation,such as targeting SC stability with pharmacological agents,nutritional strategies,or gene therapy,and employing mitochondrial transplantation in cases of severe mitochondrial failure.Precision medicine approaches,incorporating multi-omics profiling and patient-derived models,may enable individualized interventions and early detection using SC integrity as a biomarker.By linking molecular mechanisms to therapeutic strategies,this review underscores the potential of mitochondrial-targeted interventions to improve outcomes in patients with liver disease.
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supported by the National Key Research and Development Program of China(2021YFA1300800)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0570000)+2 种基金the National Natural Science Foundation of China(32271300)the Committee of Science and Technology in Shanghai(22ZR1481300,22JC1400503)the CAS Project for Young Scientists in Basic Research(YSBR-075).
文摘Mitochondria are cellular organelles that originate from an endosymbiotic bacterial ancestor and are primarily responsible for ATP generation via oxidative phosphorylation(OXPHOS).OXPHOS is conducted by five mitochondrial respiratory complexes in the inner mitochondrial membrane.Human mitochondria possess a distinct genome,a small,circular,double-stranded DNA(mtDNA)of 16,569 base pairs.This genome encodes 37 genes.
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 funding from the Max Planck Society(S.M.J.,A.G.,A.R.F.,and Y.Z.)the European Union’s Horizon 2020 research and innovation program,project PlantaSYST(SGA-CSA no.739582 under FPA no.664620)for supporting their researchfinancial support from the IMPRS-PMPG program.
文摘Protein complexes are important for almost all biological processes.Hence,to fully understand how cells work,it is also necessary to characterize protein complexes and their dynamics in response to various cellular cues.Moreover,the dynamics of protein interaction play crucial roles in regulating the(dis)association of protein complexes and,in turn,regulating biological processes such as metabolism.Here,mitochondrial protein complexes were investigated by blue native PAGE and size-exclusion chromatography under conditions of oxidative stress in order to monitor their dynamic(dis)associations.Rearrangements of enzyme interactions and changes in protein complex abundance were observed in response to oxidative stress induced by menadione treatment.These included changes in enzymatic protein complexes involving g-amino butyric acid transaminase(GABA-T),D-ornithine aminotransferase(D-OAT),or proline dehydrogenase 1(POX1)that are expected to affect proline metabolism.Menadione treatment also affected interactions between several enzymes of the tricarboxylic acid(TCA)cycle and the abundance of complexes of the oxidative phosphorylation pathway.In addition,we compared the mitochondrial complexes of roots and shoots.Considerable differences between the two tissues were observed in the mitochondrial import/export apparatus,the formation of super-complexes in the oxidative phosphorylation pathway,and specific interactions between enzymes of the TCA cycle that we postulate may be related to the metabolic/energetic requirements of roots and shoots.
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.
