Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in ...Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in macrophages, specifically an increase in aerobic glycolysis, which is linked to heightened inflammatory responses. This suggests that targeting macrophage metabolism could offer a new therapeutic avenue. In this study, we developed an immunometabolic intervention using quercetin (Q) encapsulated in bioadhesive mesoporous polydopamine (Q@MPDA) to treat periodontitis. Our results demonstrated that Q@MPDA could reprogram inflammatory macrophages to an anti-inflammatory phenotype (i.e., from-M1-to-M2 repolarization). In a murine periodontitis model, locally administered Q@MPDA reduced the presence of inflammatory macrophages, and decreased the levels of inflammatory cytokines (IL-1β and TNF-α) and reactive oxygen species (ROS) in the periodontium. Consequently, it alleviated periodontitis symptoms, reduced alveolar bone loss, and promoted tissue repair. Furthermore, our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory macrophages while enhancing oxidative phosphorylation (OXPHOS), facilitating the shift from M1 to M2 macrophage subtype. Our findings suggest that Q@MPDA is a promising treatment for periodontitis via immunometabolic rewiring.展开更多
Objectives Exercise training induces several skeletal muscle adaptations.Beta-guanidinopropionic acid(β-GPA)is a creatine analog that simulates the effect of exercise to induce mitochondrial biogenesis.However,the ef...Objectives Exercise training induces several skeletal muscle adaptations.Beta-guanidinopropionic acid(β-GPA)is a creatine analog that simulates the effect of exercise to induce mitochondrial biogenesis.However,the effects ofβ-GPA on resistance training adaptation,such as muscle hypertrophy and mitochondrial biogenesis,are unclear.Therefore,using a resistance exercise model in rats,the present study was designed to investigate the effects ofβ-GPA administration on resistance training adaptations.Methods This study was approved by the Ethics Committee for Animal Experiments at Ritsumeikan University(approval number:BKC2022-009).Male Sprague Dawley rats were randomly divided into placebo orβ-GPA groups.β-GPA(1000 mg/kg)was orally administered once daily,starting seven days before the initiation of electromyostimulation as a model for resistance exercise,and continued throughout the training period.Electromyostimulation was applied to the right gastrocnemius muscle via electrical stimulation every other day for a total of 12 sessions Results Peroxisome proliferators-activated receptor-γco-activator-1α,a regulator of mitochondrial biogenesis,was significantly increased by the combination of training andβ-GPA compared to the training leg(p<0.05).Protein expression of Total OXPHOS,a marker of mitochondrial content,was significantly increased by the combination of training andβ-GPA compared to the training leg(p<0.05).β-GPA intake reduced muscle mass(main effect ofβ-GPA,p<0.05)and was associated with muscle protein breakdown-related Fbx32 and LC3-II protein expression levels but did not counteract the increase in muscle mass caused by resistance training.Conclusions Administration of exogenousβ-GPA enhanced resistance training-induced mitochondrial biogenesis.Moreover,β-GPA still permitted resistance electromyostimulation-induced muscle mass gains,but that effect was attenuated as compared to placebo.展开更多
Objective:Mitochondria play multifunctional roles in carcinogenesis.Deciphering uncertainties of molecular interactions within mitochondria will promote further understanding of cancer.Interleukin enhancer binding fac...Objective:Mitochondria play multifunctional roles in carcinogenesis.Deciphering uncertainties of molecular interactions within mitochondria will promote further understanding of cancer.Interleukin enhancer binding factor 2(ILF2)is upregulated in several malignancies,however,much remains unknown regarding ILF2 in small cell lung cancer(SCLC).In the current study,we explored ILF2's role in SCLC and demonstrated its importance in mitochondria quality control.Methods:Colony formation,cell proliferation,cell viability and xenograft studies were performed to examine ILF2's role on SCLC progression.Glucose uptake,lactate production,cellular oxygen consumption rate and extracellular acidification rate were measured to examine the effect of ILF2 on glucose metabolism.RNA-sequencing was utilized to explore genes regulated by ILF2.E2 F1 transcriptional activity was determined by dual luciferase reporter assay.Mitochondria quantification and mitochondrial membrane potential assays were performed to examine mitochondrial quality.Gene expression was determined by RT-qPCR,Western blot and IHC assay.Results:ILF2 promotes SCLC tumor growth in vitro and in vivo.ILF2 elevates oxidative phosphorylation expression and declines glucose intake and lactate production.Genome-wide analysis of ILF2 targets identified a cohort of genes regulated by E2 F1.In consistent with this,we found ILF2 interacts with E2 F1 in SCLC cells.Further studies demonstrated that suppression of E2 F1 expression could reverse ILF2-induced tumor growth and enhanced mitochondria function.Significantly,expression of ILF2 is progressively increased during SCLC progression and high ILF2 expression is correlated with higher histologic grades,which indicates ILF2's oncogenic role in SCLC.Conclusions:Our results demonstrate that ILF2 interacts with E2 F1 to maintain mitochondria quality and confers SCLC cells growth advantage in tumorigenesis.展开更多
Objective In this study,the combined effect of two stressors,namely,electromagnetic fields(EMFs)from mobile phones and fructose consumption,on hypothalamic and hepatic master metabolic regulators of the AMPK/SIRT1-UCP...Objective In this study,the combined effect of two stressors,namely,electromagnetic fields(EMFs)from mobile phones and fructose consumption,on hypothalamic and hepatic master metabolic regulators of the AMPK/SIRT1-UCP2/FOXO1 pathway were elucidated to delineate the underlying molecular mechanisms of insulin resistance.Methods Weaned Wistar rats(28 days old)were divided into 4 groups:Normal,Exposure Only(ExpO),Fructose Only(FruO),and Exposure and Fructose(EF).Each group was provided standard laboratory chow ad libitum for 8 weeks.Additionally,the control groups,namely,the Normal and FruO groups,had unrestricted access to drinking water and fructose solution(15%),respectively.Furthermore,the respective treatment groups,namely,the ExpO and EF groups,received EMF exposure(1,760 MHz,2 h/day x 8 weeks).In early adulthood,mitochondrial function,insulin receptor signaling,and oxidative stress signals in hypothalamic and hepatic tissues were assessed using western blotting and biochemical analysis.Result In the hypothalamic tissue of EF,SIRT1,FOXO 1,p-PI3K,p-AKT,ComplexⅢ,UCP2,MnSOD,and catalase expressions and OXPHOS and GSH activities were significantly decreased(P<0.05)compared to the Normal,ExpO,and FruO groups.In hepatic tissue of EF,the p-AMPKα,SIRT1,FOXO1,IRS1,p-PI3K,ComplexⅠ,Ⅱ,Ⅲ,Ⅳ,Ⅴ,UCP2,and MnSOD expressions and the activity of OXPHOS,SOD,catalase,and GSH were significantly reduced compared to the Normal group(P<0.05).Conclusion The findings suggest that the combination of EMF exposure and fructose consumption during childhood and adolescence in Wistar rats disrupts the closely interlinked and multi-regulated crosstalk of insulin receptor signals,mitochondrial OXPHOS,and the antioxidant defense system in the hypothalamus and liver.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
Peroxisome proliferator-activated receptor-γ coactivator 1α（PGC-1α） is a transcriptional co-activator involved in mitochondrial biogenesis, respiratory capacity, and oxidative phosphorylation（OXPHOS）. PGC-1α p...Peroxisome proliferator-activated receptor-γ coactivator 1α（PGC-1α） is a transcriptional co-activator involved in mitochondrial biogenesis, respiratory capacity, and oxidative phosphorylation（OXPHOS）. PGC-1α plays an important role in cellular metabolism and is associated with tumorigenesis, suggesting an involvement in cell cycle progression. However, the underlying mechanisms mediating its involvement in these processes remain unclear. To elucidate the signaling pathways involved in PGC-1α function, we established a cell line, CH1 PGC-1α, which stably overexpresses PGC-1α. Using this cell line, we found that over-expression of PGC-1α stimulated extra adenosine triphosphate（ATP） and reduced reactive oxygen species（ROS） production. These effects were accompanied by up-regulation of the cell cycle checkpoint regulators Cyclin D1 and Cyclin B1. We hypothesized that ATP and ROS function as cellular signals to regulate cyclins and control cell cycle progression. Indeed, we found that reduction of ATP levels down-regulated Cyclin D1 but not Cyclin B1, whereas elevation of ROS levels down-regulated Cyclin B1 but not Cyclin D1. Furthermore, both low ATP levels and elevated ROS levels inhibited cell growth, but PGC-1α was maintained at a constant level. Together, these results demonstrate that PGC-1α regulates cell cycle progression through modulation of Cyclin D1 and Cyclin B1 by ATP and ROS. These findings suggest that PGC-1α potentially coordinates energy metabolism together with the cell cycle.展开更多
LncRNAs and metabolism represents two factors involved in cancer initiation and progression.However,the interaction between lncRNAs and metabolism remains to be fully explored.In this study,lncRNA FEZF1-AS1(FEZF1-AS1)...LncRNAs and metabolism represents two factors involved in cancer initiation and progression.However,the interaction between lncRNAs and metabolism remains to be fully explored.In this study,lncRNA FEZF1-AS1(FEZF1-AS1)was found upregulated in colon cancer after screening all the lncRNAs of colon cancer tissues deposited in TCGA,the result of which was further confirmed by RNAscope staining on a colon tissue chip.The results obtained using FEZF1-AS1 knockout colon cancer cells(SW480 KO and HCT-116 KO)constructed using CRISPR/Cas9 system confirmed the proliferation,invasion,and migration-promoting function of FEZF1-AS1 in vitro.Mechanistically,FEZF1-AS1 associated with the mitochondrial protein phosphoenolpyruvate carboxykinase(PCK2),which plays an essential role in regulating energy metabolism in the mitochondria.Knockdown of FEZF1-AS1 greatly decreased PCK2 protein levels,broke the homeostasis of energy metabolism in the mitochondria,and inhibited proliferation,invasion,and migration of SW480 and HCT-116 cells.PCK2 overexpression in FEZF1-AS1 knockout cells partially rescued the tumor inhibitory effect on colon cancer cells both in vitro and in vivo.Moreover,PCK2 overexpression specifically rescued the abnormal accumulation of Flavin mononucleotide(FMN)and succinate,both of which play an important role in oxidative phosphorylation(OXPHOS).Overall,these results indicate that FEZF1-AS1 is an oncogene through regulating energy metabolism of the cell.This research reveals a new mechanism for lncRNAs to regulate colon cancer and provides a potential target for colon cancer diagnosis and treatment.展开更多
In a recent study published in Nature,Ryu et al.1demonstrate the presence of metabolically distinct mitochondrial subpopulations within one cell.One mitochondrial subpopulation contains the FiFo-ATP synthase for oxida...In a recent study published in Nature,Ryu et al.1demonstrate the presence of metabolically distinct mitochondrial subpopulations within one cell.One mitochondrial subpopulation contains the FiFo-ATP synthase for oxidative phosphorylation(OXPHOS),while a second population performs reductive biosynthesis of proline and ornithine.The separation of mitochondria into two functionally distinct pools is reversible and depends on their fusion and fission.展开更多
Aim:Mutations in the mitochondrial(mt)genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells.This study explores the mutational stat...Aim:Mutations in the mitochondrial(mt)genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells.This study explores the mutational status of the mt genome of cisplatin-resistant vs.-sensitive testicular germ cell tumor(TGCT)cells and explores its association with their respiration parameters,expression of respiratory genes,and preferences for metabolic pathways to reveal new markers of therapy resistance in TGCTs.Methods:Using Illumina sequencing with Twist Enrichment Panel,the mutations of mt genomes of sensitive 2102EP,H12.1,NTERA-2,T-cam and resistant 2102EP Cis,H12.1 ODM,1411HP,1777NRpmet,NTERA-2 Cis and T-cam Cis cell lines were identified.The mt respiration of the cells was assessed using high-resolution respirometry method(O2k-respirometer Oroboros)and the differential expression profiles of mt respiratory genes were determined using RT-qPCR.Associated preferences for metabolic pathways were compared using Glycolysis/OXPHOS assay.Results:In resistant TGCT cells,new mutations in mt genes MT-ND1-6,MT-RNR,MT-CO1-3,MT-ATP6,and MT-CYB were recognized.The respiratory rates of the 1777NRpmet cell line were the highest,while those of the 1411HP line the lowest;rates of the control and all other TGCT cell lines fell between these two lines.The statistically significant differences in gene expression of the respiratory genes were recorded only in NTERA-2 Cis and T-cam Cis cell lines.Sensitive cell lines NTERA-2 and 2102EP preferred oxidative phosphorylation(OXPHOS),while glycolysis was typical for resistant NTERA-2 Cis,2102EP Cis and 1411HP cell lines.Metastatic 1777NRpmet cells seem to utilize both.An isogenic pair of cell lines H12.1 and H12.1ODM showed the opposite dependence,sensitive H12.1 preferring glycolysis,while resistant H12.1ODM OXPHOS.Conclusion:In summary,our study identified new mutations in mt genes of resistant TGCT cell lines that are associated with different mt respiration parameters,gene expression patterns and preferences for metabolic pathways,providing potential novel molecular biomarkers that distinguish the resistant TGCT phenotype or specify its histological classification.展开更多
Zinc finger in the cerebellum 1 （Zicl） is known to regulate neurogenesis and myogenesis in the develop- mental stage and widely used as one of the brown adipocyte-specific markers. In this study, we examined the eff...Zinc finger in the cerebellum 1 （Zicl） is known to regulate neurogenesis and myogenesis in the develop- mental stage and widely used as one of the brown adipocyte-specific markers. In this study, we examined the effect of Zicl on brown adipogenesis. Overexpression of Zicl attenuated the lipid accumulation and the expressions of PPAR72 and C/EBPα in C3H10T1/2 mesenchymal stem cells. The mRNA levels of BAT-specific thermogenic genes （PRDM16, PGC-1α and UCP1） and fatty acid oxidation regulatory genes （PPARα, CPT1α, CPT1β and COX7α1） were suppressed in Zicl-overexpressed cells. Moreover, overexpression of Zicl reduced the mitochondrial oxidative phosphorylation （OXPHOS） regulatory proteins including ATP5α, UQCRC2, SDHB and NDUFB5. These results indicate a potential role of Zicl in the regulation of brown adipogenesis via inhibiting adipogenesis, fatty acid oxidation and mitochondrial OXPHOS.展开更多
Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic intervention...Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.展开更多
T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation,which serves as an excellent example to dissect the metabolic basis of cell fate decisio...T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation,which serves as an excellent example to dissect the metabolic basis of cell fate decisions.During the last decade,there has been an explosion of research into the metabolic control of T-cell responses.The roles of common metabolic pathways,including glycolysis,lipid metabolism,and mitochondrial oxidative phosphorylation,in T-cell responses have been well characterized,and their mechanisms of action are starting to emerge.In this review,we present several considerations for T-cell metabolism-focused research,while providing an overview of the metabolic control of T-cell fate decisions during their life journey.We try to synthesize principles that explain the causal relationship between cellular metabolism and T-cell fate decision.We also discuss key unresolved questions and challenges in targeting T-cell metabolism to treat disease.展开更多
Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hemato...Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy;we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.展开更多
基金National Key Research and Development Program of China(2022YFE0203600,China)National Nature Science Foundation of China(82271028,82341232)+5 种基金Department of Science and Technology of Guangdong Province(High-level New R&D Institute 2019B090904008,High-level Innovative Research Institute 2021B0909050003,China)Zhongshan Municipal Bureau of Science and Technology(LJ2021001&CXTD2022011,China)It also supported by the Project of Biobank(YBKB202102,China)Research Discipline Fund(KQYJXK2020,China)Cross-disciplinary Research Fund(JYJC202205,China)from Shanghai Ninth People's Hospital(SHSMU-ZDCX20212500,China)Shanghai Pujiang Program(22PJD038,China).
文摘Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in macrophages, specifically an increase in aerobic glycolysis, which is linked to heightened inflammatory responses. This suggests that targeting macrophage metabolism could offer a new therapeutic avenue. In this study, we developed an immunometabolic intervention using quercetin (Q) encapsulated in bioadhesive mesoporous polydopamine (Q@MPDA) to treat periodontitis. Our results demonstrated that Q@MPDA could reprogram inflammatory macrophages to an anti-inflammatory phenotype (i.e., from-M1-to-M2 repolarization). In a murine periodontitis model, locally administered Q@MPDA reduced the presence of inflammatory macrophages, and decreased the levels of inflammatory cytokines (IL-1β and TNF-α) and reactive oxygen species (ROS) in the periodontium. Consequently, it alleviated periodontitis symptoms, reduced alveolar bone loss, and promoted tissue repair. Furthermore, our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory macrophages while enhancing oxidative phosphorylation (OXPHOS), facilitating the shift from M1 to M2 macrophage subtype. Our findings suggest that Q@MPDA is a promising treatment for periodontitis via immunometabolic rewiring.
基金supported by JSPS KAKENHI Grant Number JP21KK0177 to SF.
文摘Objectives Exercise training induces several skeletal muscle adaptations.Beta-guanidinopropionic acid(β-GPA)is a creatine analog that simulates the effect of exercise to induce mitochondrial biogenesis.However,the effects ofβ-GPA on resistance training adaptation,such as muscle hypertrophy and mitochondrial biogenesis,are unclear.Therefore,using a resistance exercise model in rats,the present study was designed to investigate the effects ofβ-GPA administration on resistance training adaptations.Methods This study was approved by the Ethics Committee for Animal Experiments at Ritsumeikan University(approval number:BKC2022-009).Male Sprague Dawley rats were randomly divided into placebo orβ-GPA groups.β-GPA(1000 mg/kg)was orally administered once daily,starting seven days before the initiation of electromyostimulation as a model for resistance exercise,and continued throughout the training period.Electromyostimulation was applied to the right gastrocnemius muscle via electrical stimulation every other day for a total of 12 sessions Results Peroxisome proliferators-activated receptor-γco-activator-1α,a regulator of mitochondrial biogenesis,was significantly increased by the combination of training andβ-GPA compared to the training leg(p<0.05).Protein expression of Total OXPHOS,a marker of mitochondrial content,was significantly increased by the combination of training andβ-GPA compared to the training leg(p<0.05).β-GPA intake reduced muscle mass(main effect ofβ-GPA,p<0.05)and was associated with muscle protein breakdown-related Fbx32 and LC3-II protein expression levels but did not counteract the increase in muscle mass caused by resistance training.Conclusions Administration of exogenousβ-GPA enhanced resistance training-induced mitochondrial biogenesis.Moreover,β-GPA still permitted resistance electromyostimulation-induced muscle mass gains,but that effect was attenuated as compared to placebo.
基金supported by the National Natural Science Foundation of China (Grant No. 81602026)the Natural Science Foundation of Tianjin (Grant No. 18JCQNJC81600 and 18JCZDJC32600)
文摘Objective:Mitochondria play multifunctional roles in carcinogenesis.Deciphering uncertainties of molecular interactions within mitochondria will promote further understanding of cancer.Interleukin enhancer binding factor 2(ILF2)is upregulated in several malignancies,however,much remains unknown regarding ILF2 in small cell lung cancer(SCLC).In the current study,we explored ILF2's role in SCLC and demonstrated its importance in mitochondria quality control.Methods:Colony formation,cell proliferation,cell viability and xenograft studies were performed to examine ILF2's role on SCLC progression.Glucose uptake,lactate production,cellular oxygen consumption rate and extracellular acidification rate were measured to examine the effect of ILF2 on glucose metabolism.RNA-sequencing was utilized to explore genes regulated by ILF2.E2 F1 transcriptional activity was determined by dual luciferase reporter assay.Mitochondria quantification and mitochondrial membrane potential assays were performed to examine mitochondrial quality.Gene expression was determined by RT-qPCR,Western blot and IHC assay.Results:ILF2 promotes SCLC tumor growth in vitro and in vivo.ILF2 elevates oxidative phosphorylation expression and declines glucose intake and lactate production.Genome-wide analysis of ILF2 targets identified a cohort of genes regulated by E2 F1.In consistent with this,we found ILF2 interacts with E2 F1 in SCLC cells.Further studies demonstrated that suppression of E2 F1 expression could reverse ILF2-induced tumor growth and enhanced mitochondria function.Significantly,expression of ILF2 is progressively increased during SCLC progression and high ILF2 expression is correlated with higher histologic grades,which indicates ILF2's oncogenic role in SCLC.Conclusions:Our results demonstrate that ILF2 interacts with E2 F1 to maintain mitochondria quality and confers SCLC cells growth advantage in tumorigenesis.
基金supported by the Indian Council of Medical Research(ICMR)in New Delhi.(Sanction NO:5/10/FR/13/2015-RBMH)。
文摘Objective In this study,the combined effect of two stressors,namely,electromagnetic fields(EMFs)from mobile phones and fructose consumption,on hypothalamic and hepatic master metabolic regulators of the AMPK/SIRT1-UCP2/FOXO1 pathway were elucidated to delineate the underlying molecular mechanisms of insulin resistance.Methods Weaned Wistar rats(28 days old)were divided into 4 groups:Normal,Exposure Only(ExpO),Fructose Only(FruO),and Exposure and Fructose(EF).Each group was provided standard laboratory chow ad libitum for 8 weeks.Additionally,the control groups,namely,the Normal and FruO groups,had unrestricted access to drinking water and fructose solution(15%),respectively.Furthermore,the respective treatment groups,namely,the ExpO and EF groups,received EMF exposure(1,760 MHz,2 h/day x 8 weeks).In early adulthood,mitochondrial function,insulin receptor signaling,and oxidative stress signals in hypothalamic and hepatic tissues were assessed using western blotting and biochemical analysis.Result In the hypothalamic tissue of EF,SIRT1,FOXO 1,p-PI3K,p-AKT,ComplexⅢ,UCP2,MnSOD,and catalase expressions and OXPHOS and GSH activities were significantly decreased(P<0.05)compared to the Normal,ExpO,and FruO groups.In hepatic tissue of EF,the p-AMPKα,SIRT1,FOXO1,IRS1,p-PI3K,ComplexⅠ,Ⅱ,Ⅲ,Ⅳ,Ⅴ,UCP2,and MnSOD expressions and the activity of OXPHOS,SOD,catalase,and GSH were significantly reduced compared to the Normal group(P<0.05).Conclusion The findings suggest that the combination of EMF exposure and fructose consumption during childhood and adolescence in Wistar rats disrupts the closely interlinked and multi-regulated crosstalk of insulin receptor signals,mitochondrial OXPHOS,and the antioxidant defense system in the hypothalamus and liver.
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.
基金supported by the National Natural Science Foundation of China(Nos.31160237 and 81360310)the Graduate Student Research Innovation Project of Yunnan University(No.YNUY201455),China
文摘Peroxisome proliferator-activated receptor-γ coactivator 1α（PGC-1α） is a transcriptional co-activator involved in mitochondrial biogenesis, respiratory capacity, and oxidative phosphorylation（OXPHOS）. PGC-1α plays an important role in cellular metabolism and is associated with tumorigenesis, suggesting an involvement in cell cycle progression. However, the underlying mechanisms mediating its involvement in these processes remain unclear. To elucidate the signaling pathways involved in PGC-1α function, we established a cell line, CH1 PGC-1α, which stably overexpresses PGC-1α. Using this cell line, we found that over-expression of PGC-1α stimulated extra adenosine triphosphate（ATP） and reduced reactive oxygen species（ROS） production. These effects were accompanied by up-regulation of the cell cycle checkpoint regulators Cyclin D1 and Cyclin B1. We hypothesized that ATP and ROS function as cellular signals to regulate cyclins and control cell cycle progression. Indeed, we found that reduction of ATP levels down-regulated Cyclin D1 but not Cyclin B1, whereas elevation of ROS levels down-regulated Cyclin B1 but not Cyclin D1. Furthermore, both low ATP levels and elevated ROS levels inhibited cell growth, but PGC-1α was maintained at a constant level. Together, these results demonstrate that PGC-1α regulates cell cycle progression through modulation of Cyclin D1 and Cyclin B1 by ATP and ROS. These findings suggest that PGC-1α potentially coordinates energy metabolism together with the cell cycle.
基金supported by the GDAS Special Project of Science and Technology Development (2019GDASYL-0103058)Guangdong Basic and Applied Basic Research Foundation,Natural Science Foundation of Guangdong Province (2019A1515011456).
文摘LncRNAs and metabolism represents two factors involved in cancer initiation and progression.However,the interaction between lncRNAs and metabolism remains to be fully explored.In this study,lncRNA FEZF1-AS1(FEZF1-AS1)was found upregulated in colon cancer after screening all the lncRNAs of colon cancer tissues deposited in TCGA,the result of which was further confirmed by RNAscope staining on a colon tissue chip.The results obtained using FEZF1-AS1 knockout colon cancer cells(SW480 KO and HCT-116 KO)constructed using CRISPR/Cas9 system confirmed the proliferation,invasion,and migration-promoting function of FEZF1-AS1 in vitro.Mechanistically,FEZF1-AS1 associated with the mitochondrial protein phosphoenolpyruvate carboxykinase(PCK2),which plays an essential role in regulating energy metabolism in the mitochondria.Knockdown of FEZF1-AS1 greatly decreased PCK2 protein levels,broke the homeostasis of energy metabolism in the mitochondria,and inhibited proliferation,invasion,and migration of SW480 and HCT-116 cells.PCK2 overexpression in FEZF1-AS1 knockout cells partially rescued the tumor inhibitory effect on colon cancer cells both in vitro and in vivo.Moreover,PCK2 overexpression specifically rescued the abnormal accumulation of Flavin mononucleotide(FMN)and succinate,both of which play an important role in oxidative phosphorylation(OXPHOS).Overall,these results indicate that FEZF1-AS1 is an oncogene through regulating energy metabolism of the cell.This research reveals a new mechanism for lncRNAs to regulate colon cancer and provides a potential target for colon cancer diagnosis and treatment.
文摘In a recent study published in Nature,Ryu et al.1demonstrate the presence of metabolically distinct mitochondrial subpopulations within one cell.One mitochondrial subpopulation contains the FiFo-ATP synthase for oxidative phosphorylation(OXPHOS),while a second population performs reductive biosynthesis of proline and ornithine.The separation of mitochondria into two functionally distinct pools is reversible and depends on their fusion and fission.
基金supported by the VEGA Grant Agency of the Slovak Republic(grant no.2/0056/21)the Slovak Research and Development Agency(grant no.APVV-19-0286)Doctoral grant of the Slovak Academy of Sciences(grant no.APP0377).
文摘Aim:Mutations in the mitochondrial(mt)genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells.This study explores the mutational status of the mt genome of cisplatin-resistant vs.-sensitive testicular germ cell tumor(TGCT)cells and explores its association with their respiration parameters,expression of respiratory genes,and preferences for metabolic pathways to reveal new markers of therapy resistance in TGCTs.Methods:Using Illumina sequencing with Twist Enrichment Panel,the mutations of mt genomes of sensitive 2102EP,H12.1,NTERA-2,T-cam and resistant 2102EP Cis,H12.1 ODM,1411HP,1777NRpmet,NTERA-2 Cis and T-cam Cis cell lines were identified.The mt respiration of the cells was assessed using high-resolution respirometry method(O2k-respirometer Oroboros)and the differential expression profiles of mt respiratory genes were determined using RT-qPCR.Associated preferences for metabolic pathways were compared using Glycolysis/OXPHOS assay.Results:In resistant TGCT cells,new mutations in mt genes MT-ND1-6,MT-RNR,MT-CO1-3,MT-ATP6,and MT-CYB were recognized.The respiratory rates of the 1777NRpmet cell line were the highest,while those of the 1411HP line the lowest;rates of the control and all other TGCT cell lines fell between these two lines.The statistically significant differences in gene expression of the respiratory genes were recorded only in NTERA-2 Cis and T-cam Cis cell lines.Sensitive cell lines NTERA-2 and 2102EP preferred oxidative phosphorylation(OXPHOS),while glycolysis was typical for resistant NTERA-2 Cis,2102EP Cis and 1411HP cell lines.Metastatic 1777NRpmet cells seem to utilize both.An isogenic pair of cell lines H12.1 and H12.1ODM showed the opposite dependence,sensitive H12.1 preferring glycolysis,while resistant H12.1ODM OXPHOS.Conclusion:In summary,our study identified new mutations in mt genes of resistant TGCT cell lines that are associated with different mt respiration parameters,gene expression patterns and preferences for metabolic pathways,providing potential novel molecular biomarkers that distinguish the resistant TGCT phenotype or specify its histological classification.
基金supported by the Strategic Priority Research Program(XDB13030000)Key Research Program(KJZD-EW-L01-3)+1 种基金the One Hundred Talents Program of the Chinese Academy of Sciences and the Ministry of Science and Technology of China(2012CBA01301 and 2012CB944701,respectively)the National Natural Science Foundation of China(31171131,81370951)
文摘Zinc finger in the cerebellum 1 （Zicl） is known to regulate neurogenesis and myogenesis in the develop- mental stage and widely used as one of the brown adipocyte-specific markers. In this study, we examined the effect of Zicl on brown adipogenesis. Overexpression of Zicl attenuated the lipid accumulation and the expressions of PPAR72 and C/EBPα in C3H10T1/2 mesenchymal stem cells. The mRNA levels of BAT-specific thermogenic genes （PRDM16, PGC-1α and UCP1） and fatty acid oxidation regulatory genes （PPARα, CPT1α, CPT1β and COX7α1） were suppressed in Zicl-overexpressed cells. Moreover, overexpression of Zicl reduced the mitochondrial oxidative phosphorylation （OXPHOS） regulatory proteins including ATP5α, UQCRC2, SDHB and NDUFB5. These results indicate a potential role of Zicl in the regulation of brown adipogenesis via inhibiting adipogenesis, fatty acid oxidation and mitochondrial OXPHOS.
基金supported by the National Natural Science Foundation of China(Nos.22007063 and 82002063)Shanxi Medical Key Science and Technology Project Plan of China(No.2020XM01)+4 种基金the National University of Singapore Start-up Grant(No.NUHSRO/2020/133/Startup/08)NUS School of Medicine Nanomedicine Translational Research Program(No.NUHSRO/2021/034/TRP/09/Nanomedicine)the Science Research Start-up Fund for Doctor of Shanxi Province(No.XD1809 and XD2011)the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(No.2019L0414)Shanxi Province Science Foundation for Youths(No.201901D211316).
文摘Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.
基金M.P.is supported by National Natural Science Foundation of China(31741085)Tsinghua University Initiative Scientific Research Program(2021Z)+2 种基金Vanke Special Fund for Public Health and Health Discipline Development,Tsinghua University(2022Z82WKJ013)Tsinghua-Peking Center for Life Sciences and Institute for Immunology at Tsinghua University.M.O.L.is supported by NIH(R01 AI 102888)a Howard Hughes Medical Institute Faculty Scholar Award and by Memorial Sloan Kettering Cancer Center Support Grant(Core Grant P30 CA08748).
文摘T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation,which serves as an excellent example to dissect the metabolic basis of cell fate decisions.During the last decade,there has been an explosion of research into the metabolic control of T-cell responses.The roles of common metabolic pathways,including glycolysis,lipid metabolism,and mitochondrial oxidative phosphorylation,in T-cell responses have been well characterized,and their mechanisms of action are starting to emerge.In this review,we present several considerations for T-cell metabolism-focused research,while providing an overview of the metabolic control of T-cell fate decisions during their life journey.We try to synthesize principles that explain the causal relationship between cellular metabolism and T-cell fate decision.We also discuss key unresolved questions and challenges in targeting T-cell metabolism to treat disease.
文摘Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy;we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.
