In most eukaryotes,oxidative phosphorylation(OXPHOS)is the main energy production process and it involves both mitochondrial and nuclear genomes.The close interaction between the two genomes is critical for the coordi...In most eukaryotes,oxidative phosphorylation(OXPHOS)is the main energy production process and it involves both mitochondrial and nuclear genomes.The close interaction between the two genomes is critical for the coordinated function of the OXPHOS process.Some bivalves show doubly uniparental inheritance(DUI)of mitochondria,where two highly divergent mitochondrial genomes,one inherited through eggs(F-type)and the other through sperm(M-type),coexist in the same individual.However,it remains a puzzle how nuclear OXPHOS genes coordinate with two divergent mitochondrial genomes in DUI species.In this study,we compared transcription,polymorphism,and synonymous codon usage in the mitochondrial and nuclear OXPHOS genes of the DUI species Ruditapes philippinarum using sex-and tissue-specific transcriptomes.Mitochondrial and nuclear OXPHOS genes showed different transcription profiles.Strong co-transcription signal was observed within mitochondrial(separate for F-and M-type)and within nuclear OXPHOS genes but the signal was weak or absent between mitochondrial and nuclear OXPHOS genes,suggesting that the coordination between mitochondrial and nuclear OXPHOS subunits is not achieved transcriptionally.McDonald-Kreitman and frequency-spectrum based tests indicated that M-type OXPHOS genes deviated significantly from neutrality,and that F-type and M-type OXPHOS genes undergo different selection patterns.Codon usage analysis revealed that mutation bias and translational selection were the major factors affecting the codon usage bias in different OXPHOS genes,nevertheless,translational selection in mitochondrial OXPHOS genes appears to be less efficient than nuclear OXPHOS genes.Therefore,we speculate that the coordination between OXPHOS genes may involve post-transcriptional/translational regulation.展开更多
Cytochalasin B(CB)was a depolymeriziner agent of F-aetin.Therefore a lot of plant cell motilities related to action,such as cytoplasmic streaming,pollen
Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generat...Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.展开更多
BACKGROUND:Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure.Endothelial cells(ECs)exhibit specific metabolic traits and release metabolites to adapt to the septic state in the ...BACKGROUND:Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure.Endothelial cells(ECs)exhibit specific metabolic traits and release metabolites to adapt to the septic state in the blood to maintain vascular homeostasis.METHODS:Web of Science and PubMed were searched from inception to October 1,2022.The search was limited to the English language only.Two reviewers independently identified studies related to EC metabolism in sepsis.The exclusion criteria were duplicate articles according to multiple search criteria.RESULTS:Sixty articles were included,and most of them were cell and animal studies.These studies reported the role of glycolysis,oxidative phosphorylation,fatty acid metabolism,and amino acid metabolism in EC homeostasis.including glycolysis,oxidative phosphorylation,fatty acid metabolism and amino acid metabolism.However,dysregulation of EC metabolism can contribute to sepsis progression.CONCLUSION:There are few clinical studies on EC metabolism in sepsis.Related research mainly focuses on basic research,but some scientific problems have also been clarified.Therefore,this review may provide an overall comprehension and novel aspects of EC metabolism in sepsis.展开更多
At the present,association of mitochondrial dysfunction and progression of neurological disorders has gained significant attention.Defects in mitochondrial network dynamics,point mutations,deletions,and interaction of...At the present,association of mitochondrial dysfunction and progression of neurological disorders has gained significant attention.Defects in mitochondrial network dynamics,point mutations,deletions,and interaction of pathogenomic proteins with mitochondria are some of the possible underlying mechanisms involved in these neurological disorders.Mitochondrial genetics,defects in mitochondrial oxidative phosphorylation machinery,and reactive oxygen species production might share common crosstalk in the progression of these neurological disorders.It is of significant interests to explore and develop therapeutic strategies aimed at correcting mitochondrial abnormalities.This review provided insights on mitochondrial dysfunction/mutations involved in the progression of Alzheimer’s disease,Huntington’s disease,and epilepsy with a special focus on Parkinson’s disease pathology.Along with the deleterious effects of mitochondrial mutations in aforesaid neurological disorders,this paper unraveled the available therapeutic strategy,specifically aiming to improve mitochondrial dysfunction,drugs targeting mitochondrial proteins,gene therapies aimed at correcting mutant mtDNA,peptide-based approaches,and lipophilic cations.展开更多
Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic dysfunction.Mitochondrial function has...Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic dysfunction.Mitochondrial function has been shown to be severely impaired during the early phase of critical illness,with a reduction in biogenesis,increased generation of reactive oxygen species and a decrease in adenosine triphosphate synthesis of up to 50%.Mitochondrial dysfunction can be assessed using mitochondrial DNA concentration and respirometry assays,particularly in peripheral mononuclear cells.Isolation of monocytes and lymphocytes seems to be the most promising strategy for measuring mitochondrial activity in clinical settings because of the ease of collection,sample processing,and clinical relevance of the association between metabolic alterations and deficient immune responses in mononuclear cells.Studies have reported alterations in these variables in patients with sepsis compared with healthy controls and non-septic patients.However,few studies have explored the association between mitochondrial dysfunction in immune mononuclear cells and unfavorable clinical outcomes.An improvement in mitochondrial parameters in sepsis could theoretically serve as a biomarker of clinical recovery and response to oxygen and vasopressor therapies as well as reveal unexplored pathophysiological mechanistic targets.These features highlight the need for further studies on mitochondrial metabolism in immune cells as a feasible tool to evaluate patients in intensive care settings.The evaluation of mitochondrial metabolism is a promising tool for the evaluation and management of critically ill patients,especially those with sepsis.In this article,we explore the pathophysiological aspects,main methods of measurement,and the main studies in this field.展开更多
Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial...Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.展开更多
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration,utilizing glucose fermentation for energy production,known as the Warburg effect.However,there are a lack of comprehensive reviews summarizing t...Cancer cells exhibit metabolic reprogramming and bioenergetic alteration,utilizing glucose fermentation for energy production,known as the Warburg effect.However,there are a lack of comprehensive reviews summarizing the metabolic reprogramming,bioenergetic alteration,and their oncogenetic links in gastrointestinal(GI)cancers.Furthermore,the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation.This review highlights the interplay between aerobic glycolysis,the tricarboxylic acid(TCA)cycle,and oxidative phosphorylation(OXPHOS)in cancer cells,as well as hypotheses on the molecular mechanisms that trigger this alteration.The role of hypoxia-inducible transcription factors,tumor suppressors,and the oncogenetic link between hypoxia-related enzymes,bioenergetic changes,and GI cancer are also discussed.This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy,particularly for GI cancers.Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy,the review categorizes these regulators into aerobic glycolysis/lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS.We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers,as well as the challenges posed by these drugs.Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments,although the diverse metabolic patterns present challenges for targeted therapies.Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes,address side effects,and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.展开更多
In platelets, most of the ADP is stored in dense granules and released into extracellular space through exocytosis as a signaling molecule upon platelet activation. Glycolysis and the TCA cycle consume considerable am...In platelets, most of the ADP is stored in dense granules and released into extracellular space through exocytosis as a signaling molecule upon platelet activation. Glycolysis and the TCA cycle consume considerable amounts of ADP;however, limiting quantities of available ADP to make ATP through OXPHOS result in failure of ATP production and release of energy as heat into the surroundings. Thus, body heat may be a potential product of circulating platelets. Furthermore, the incomplete OXPHOS process causes the production of ROS that leads to earlier platelet death resulting in shorter life span. In the future, this new function may have a wide variety of clinical applications.展开更多
The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has b...The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.展开更多
Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumo...Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumor relapse is thought to be caused by the presence of these cells.CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies.Additionally,the metabolic properties of cancer cells differ markedly from those of normal cells.The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells.Metabolic targeting of breast CSCs(BCSCs)may be a very effective strategy for anti-cancer treatment of breast cancer cells.Thus,in this review,we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.展开更多
Background:Heterosis is an important biological phenomenon that has been extensively utilized in agricultural breeding.However,negative heterosis is also pervasively observed in nature,which can cause unfavorable impa...Background:Heterosis is an important biological phenomenon that has been extensively utilized in agricultural breeding.However,negative heterosis is also pervasively observed in nature,which can cause unfavorable impacts on production performance.Compared with systematic studies of positive heterosis,the phenomenon of negative heterosis has been largely ignored in genetic studies and breeding programs,and the genetic mechanism of this phenomenon has not been thoroughly elucidated to date.Here,we used chickens,the most common agricultural animals worldwide,to determine the genetic and molecular mechanisms of negative heterosis.Results:We performed reciprocal crossing experiments with two distinct chicken lines and found that the body weight presented widely negative heterosis in the early growth of chickens.Negative heterosis of carcass traits was more common than positive heterosis,especially breast muscle mass,which was over−40%in reciprocal progenies.Genome-wide gene expression pattern analyses of breast muscle tissues revealed that nonadditivity,including dominance and overdominace,was the major gene inheritance pattern.Nonadditive genes,including a substantial number of genes encoding ATPase and NADH dehydrogenase,accounted for more than 68%of differentially expressed genes in reciprocal crosses(4257 of 5587 and 3617 of 5243,respectively).Moreover,nonadditive genes were significantly associated with the biological process of oxidative phosphorylation,which is the major metabolic pathway for energy release and animal growth and development.The detection of ATP content and ATPase activity for purebred and crossbred progenies further confirmed that chickens with lower muscle yield had lower ATP concentrations but higher hydrolysis activity,which supported the important role of oxidative phosphorylation in negative heterosis for growth traits in chickens.Conclusions:These findings revealed that nonadditive genes and their related oxidative phosphorylation were the major genetic and molecular factors in the negative heterosis of growth in chickens,which would be beneficial to future breeding strategies.展开更多
Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen.In contrast,most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules.Cance...Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen.In contrast,most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules.Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth.A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells(CSCs).New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells.CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism.The mechanism of the metabolic plasticity of CSCs has not been fully elucidated,and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment.Targeting CSC metabolism may provide new and effective methods for the treatment of tumors.In this review,we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs,and discuss the clinical implications of targeting CSC metabolism.展开更多
In a recent article Fu et al reported about a 52 years old female with a mitochondrial disorder due to the variant m.10158T>C in the mtDNA located gene MT-ND3.The study has a number of shortcomings.The study would ...In a recent article Fu et al reported about a 52 years old female with a mitochondrial disorder due to the variant m.10158T>C in the mtDNA located gene MT-ND3.The study has a number of shortcomings.The study would particularly profit from providing more data about multisystem disease,from providing the current medication,the cerebro-spinal fluid findings,the detailed phenotypic presentation,and the genotype of first-degree relatives.Since the index patient had experienced recurrent seizures it is crucial to know the current and previous anti-seizure medication as it may strongly determine the outcome.Some of them are mitochondrion-toxic and particularly valproic acid may exhibit fatal side effects.The outcome may also depend on the degree of multisystem involvement why it is crucial to prospectively investigate the patient for subclinical involvement of organs not obviously affected.Additionally,the outcome of the stroke-like lesions on imaging would be interesting to see.Strokelike lesions may completely disappear or may end up as white matter lesion,laminar cortical necrosis,focal atrophy,cyst,or as the so-called toenail sign.There is also a need of discussing more profoundly the imaging findings and their diagnostic significance and to investigate first degree relatives of the index patient clinically and genetically.Though highly interesting,the presentation of this case of a mitochondrial disorder lacks clinical and genetic data of the patient and his relatives.Outcome parameters,such as severity of disease,degree of progression,drugs,pathogenicity of the mutation,and multisystem involvement require a profound discussion.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
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
Metabolic reprogramming,a newly recognized trait of tumor biology,is an intensively studied prospect for oncology medicines.For numerous tumors and cancer cell subpopulations,oxidative phosphorylation(OXPHOS)is essent...Metabolic reprogramming,a newly recognized trait of tumor biology,is an intensively studied prospect for oncology medicines.For numerous tumors and cancer cell subpopulations,oxidative phosphorylation(OXPHOS)is essential for their biosynthetic and bioenergetic functions.Cancer cells with mutations in isocitrate dehydrogenase 1(IDH1)exhibit differentiation arrest,epigenetic and transcriptional reprogramming,and sensitivity to mitochondrial OXPHOS inhibitors.In this study,we report that berberine,which is widely used in China to treat intestinal infections,acted solely at the mitochondrial electron transport chain(ETC)complex I,and that its association with IDH1 mutant inhibitor(IDH1^(m)i)AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro and in vivo.Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia(AML)patients using combinatory mitochondrial targeted medicines,particularly those who are resistant to or relapsing from IDH1m i.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
基金supported by the China Scholarship Council,Italian Ministry of Education University and Research(MIUR)FIR2013 Programme(RBFR13T97A to F.G.)MIUR SIR Programme(RBSI14G0P5 to L.M.)Canziani Bequest to F.G.,and“Ricerca Fondamentale Orientata”(RFO)from the University of Bologna to F.G.and L.M.
文摘In most eukaryotes,oxidative phosphorylation(OXPHOS)is the main energy production process and it involves both mitochondrial and nuclear genomes.The close interaction between the two genomes is critical for the coordinated function of the OXPHOS process.Some bivalves show doubly uniparental inheritance(DUI)of mitochondria,where two highly divergent mitochondrial genomes,one inherited through eggs(F-type)and the other through sperm(M-type),coexist in the same individual.However,it remains a puzzle how nuclear OXPHOS genes coordinate with two divergent mitochondrial genomes in DUI species.In this study,we compared transcription,polymorphism,and synonymous codon usage in the mitochondrial and nuclear OXPHOS genes of the DUI species Ruditapes philippinarum using sex-and tissue-specific transcriptomes.Mitochondrial and nuclear OXPHOS genes showed different transcription profiles.Strong co-transcription signal was observed within mitochondrial(separate for F-and M-type)and within nuclear OXPHOS genes but the signal was weak or absent between mitochondrial and nuclear OXPHOS genes,suggesting that the coordination between mitochondrial and nuclear OXPHOS subunits is not achieved transcriptionally.McDonald-Kreitman and frequency-spectrum based tests indicated that M-type OXPHOS genes deviated significantly from neutrality,and that F-type and M-type OXPHOS genes undergo different selection patterns.Codon usage analysis revealed that mutation bias and translational selection were the major factors affecting the codon usage bias in different OXPHOS genes,nevertheless,translational selection in mitochondrial OXPHOS genes appears to be less efficient than nuclear OXPHOS genes.Therefore,we speculate that the coordination between OXPHOS genes may involve post-transcriptional/translational regulation.
文摘Cytochalasin B(CB)was a depolymeriziner agent of F-aetin.Therefore a lot of plant cell motilities related to action,such as cytoplasmic streaming,pollen
基金supported by NIH Grant Al-15614 (to CAD)the Ministerio de Ciencia e Innovacion (PID2020-120267BRI00AEI/10.13039/501100011033)(to RLV)。
文摘Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.
基金supported by the National Natural Science Foundation of China(82272236)Key Emergency Medical Disciplines and Specialities Program of Guangzhou(2021-2023)。
文摘BACKGROUND:Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure.Endothelial cells(ECs)exhibit specific metabolic traits and release metabolites to adapt to the septic state in the blood to maintain vascular homeostasis.METHODS:Web of Science and PubMed were searched from inception to October 1,2022.The search was limited to the English language only.Two reviewers independently identified studies related to EC metabolism in sepsis.The exclusion criteria were duplicate articles according to multiple search criteria.RESULTS:Sixty articles were included,and most of them were cell and animal studies.These studies reported the role of glycolysis,oxidative phosphorylation,fatty acid metabolism,and amino acid metabolism in EC homeostasis.including glycolysis,oxidative phosphorylation,fatty acid metabolism and amino acid metabolism.However,dysregulation of EC metabolism can contribute to sepsis progression.CONCLUSION:There are few clinical studies on EC metabolism in sepsis.Related research mainly focuses on basic research,but some scientific problems have also been clarified.Therefore,this review may provide an overall comprehension and novel aspects of EC metabolism in sepsis.
文摘At the present,association of mitochondrial dysfunction and progression of neurological disorders has gained significant attention.Defects in mitochondrial network dynamics,point mutations,deletions,and interaction of pathogenomic proteins with mitochondria are some of the possible underlying mechanisms involved in these neurological disorders.Mitochondrial genetics,defects in mitochondrial oxidative phosphorylation machinery,and reactive oxygen species production might share common crosstalk in the progression of these neurological disorders.It is of significant interests to explore and develop therapeutic strategies aimed at correcting mitochondrial abnormalities.This review provided insights on mitochondrial dysfunction/mutations involved in the progression of Alzheimer’s disease,Huntington’s disease,and epilepsy with a special focus on Parkinson’s disease pathology.Along with the deleterious effects of mitochondrial mutations in aforesaid neurological disorders,this paper unraveled the available therapeutic strategy,specifically aiming to improve mitochondrial dysfunction,drugs targeting mitochondrial proteins,gene therapies aimed at correcting mutant mtDNA,peptide-based approaches,and lipophilic cations.
基金the Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul,No.1010267.
文摘Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic dysfunction.Mitochondrial function has been shown to be severely impaired during the early phase of critical illness,with a reduction in biogenesis,increased generation of reactive oxygen species and a decrease in adenosine triphosphate synthesis of up to 50%.Mitochondrial dysfunction can be assessed using mitochondrial DNA concentration and respirometry assays,particularly in peripheral mononuclear cells.Isolation of monocytes and lymphocytes seems to be the most promising strategy for measuring mitochondrial activity in clinical settings because of the ease of collection,sample processing,and clinical relevance of the association between metabolic alterations and deficient immune responses in mononuclear cells.Studies have reported alterations in these variables in patients with sepsis compared with healthy controls and non-septic patients.However,few studies have explored the association between mitochondrial dysfunction in immune mononuclear cells and unfavorable clinical outcomes.An improvement in mitochondrial parameters in sepsis could theoretically serve as a biomarker of clinical recovery and response to oxygen and vasopressor therapies as well as reveal unexplored pathophysiological mechanistic targets.These features highlight the need for further studies on mitochondrial metabolism in immune cells as a feasible tool to evaluate patients in intensive care settings.The evaluation of mitochondrial metabolism is a promising tool for the evaluation and management of critically ill patients,especially those with sepsis.In this article,we explore the pathophysiological aspects,main methods of measurement,and the main studies in this field.
文摘Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.
基金Ministry of Science and Technology,Taiwan,No.MOST-110-2314-B-182A-095-and No.MOST-111-2314-B-182A-126-(to Lin WR)and Chang Gung Memorial Hospital,Linkou Branch,Taiwan,No.CMRPG3K2292,No.CMRPG3J0693(to Lin WR),No.CORPG3J0531,No.CORPG3L0261,No.CORPG3J0501,and No.CMRPG3K0771(to Chen CW).
文摘Cancer cells exhibit metabolic reprogramming and bioenergetic alteration,utilizing glucose fermentation for energy production,known as the Warburg effect.However,there are a lack of comprehensive reviews summarizing the metabolic reprogramming,bioenergetic alteration,and their oncogenetic links in gastrointestinal(GI)cancers.Furthermore,the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation.This review highlights the interplay between aerobic glycolysis,the tricarboxylic acid(TCA)cycle,and oxidative phosphorylation(OXPHOS)in cancer cells,as well as hypotheses on the molecular mechanisms that trigger this alteration.The role of hypoxia-inducible transcription factors,tumor suppressors,and the oncogenetic link between hypoxia-related enzymes,bioenergetic changes,and GI cancer are also discussed.This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy,particularly for GI cancers.Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy,the review categorizes these regulators into aerobic glycolysis/lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS.We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers,as well as the challenges posed by these drugs.Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments,although the diverse metabolic patterns present challenges for targeted therapies.Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes,address side effects,and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
文摘In platelets, most of the ADP is stored in dense granules and released into extracellular space through exocytosis as a signaling molecule upon platelet activation. Glycolysis and the TCA cycle consume considerable amounts of ADP;however, limiting quantities of available ADP to make ATP through OXPHOS result in failure of ATP production and release of energy as heat into the surroundings. Thus, body heat may be a potential product of circulating platelets. Furthermore, the incomplete OXPHOS process causes the production of ROS that leads to earlier platelet death resulting in shorter life span. In the future, this new function may have a wide variety of clinical applications.
文摘The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.
文摘Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumor relapse is thought to be caused by the presence of these cells.CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies.Additionally,the metabolic properties of cancer cells differ markedly from those of normal cells.The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells.Metabolic targeting of breast CSCs(BCSCs)may be a very effective strategy for anti-cancer treatment of breast cancer cells.Thus,in this review,we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.
基金supported by the National Natural Science Foundation of China(No.31930105)China Agriculture Research Systems(CARS-40)China Postdoctoral Science Foundation(No.2020 M680028).
文摘Background:Heterosis is an important biological phenomenon that has been extensively utilized in agricultural breeding.However,negative heterosis is also pervasively observed in nature,which can cause unfavorable impacts on production performance.Compared with systematic studies of positive heterosis,the phenomenon of negative heterosis has been largely ignored in genetic studies and breeding programs,and the genetic mechanism of this phenomenon has not been thoroughly elucidated to date.Here,we used chickens,the most common agricultural animals worldwide,to determine the genetic and molecular mechanisms of negative heterosis.Results:We performed reciprocal crossing experiments with two distinct chicken lines and found that the body weight presented widely negative heterosis in the early growth of chickens.Negative heterosis of carcass traits was more common than positive heterosis,especially breast muscle mass,which was over−40%in reciprocal progenies.Genome-wide gene expression pattern analyses of breast muscle tissues revealed that nonadditivity,including dominance and overdominace,was the major gene inheritance pattern.Nonadditive genes,including a substantial number of genes encoding ATPase and NADH dehydrogenase,accounted for more than 68%of differentially expressed genes in reciprocal crosses(4257 of 5587 and 3617 of 5243,respectively).Moreover,nonadditive genes were significantly associated with the biological process of oxidative phosphorylation,which is the major metabolic pathway for energy release and animal growth and development.The detection of ATP content and ATPase activity for purebred and crossbred progenies further confirmed that chickens with lower muscle yield had lower ATP concentrations but higher hydrolysis activity,which supported the important role of oxidative phosphorylation in negative heterosis for growth traits in chickens.Conclusions:These findings revealed that nonadditive genes and their related oxidative phosphorylation were the major genetic and molecular factors in the negative heterosis of growth in chickens,which would be beneficial to future breeding strategies.
基金National Natural Science Foundation of China,No.81502564 and No.81972598the Natural Science Foundation of Zhejiang Province,No.LY19H160004.
文摘Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen.In contrast,most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules.Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth.A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells(CSCs).New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells.CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism.The mechanism of the metabolic plasticity of CSCs has not been fully elucidated,and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment.Targeting CSC metabolism may provide new and effective methods for the treatment of tumors.In this review,we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs,and discuss the clinical implications of targeting CSC metabolism.
文摘In a recent article Fu et al reported about a 52 years old female with a mitochondrial disorder due to the variant m.10158T>C in the mtDNA located gene MT-ND3.The study has a number of shortcomings.The study would particularly profit from providing more data about multisystem disease,from providing the current medication,the cerebro-spinal fluid findings,the detailed phenotypic presentation,and the genotype of first-degree relatives.Since the index patient had experienced recurrent seizures it is crucial to know the current and previous anti-seizure medication as it may strongly determine the outcome.Some of them are mitochondrion-toxic and particularly valproic acid may exhibit fatal side effects.The outcome may also depend on the degree of multisystem involvement why it is crucial to prospectively investigate the patient for subclinical involvement of organs not obviously affected.Additionally,the outcome of the stroke-like lesions on imaging would be interesting to see.Strokelike lesions may completely disappear or may end up as white matter lesion,laminar cortical necrosis,focal atrophy,cyst,or as the so-called toenail sign.There is also a need of discussing more profoundly the imaging findings and their diagnostic significance and to investigate first degree relatives of the index patient clinically and genetically.Though highly interesting,the presentation of this case of a mitochondrial disorder lacks clinical and genetic data of the patient and his relatives.Outcome parameters,such as severity of disease,degree of progression,drugs,pathogenicity of the mutation,and multisystem involvement require a profound discussion.
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.
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supported by Sichuan Science and Technology Program(No.2022YFS0622)the Science and Technology Development Fund,Macao SAR(Nos.0036/2020/A1 and 0013/2019/A1).
文摘Metabolic reprogramming,a newly recognized trait of tumor biology,is an intensively studied prospect for oncology medicines.For numerous tumors and cancer cell subpopulations,oxidative phosphorylation(OXPHOS)is essential for their biosynthetic and bioenergetic functions.Cancer cells with mutations in isocitrate dehydrogenase 1(IDH1)exhibit differentiation arrest,epigenetic and transcriptional reprogramming,and sensitivity to mitochondrial OXPHOS inhibitors.In this study,we report that berberine,which is widely used in China to treat intestinal infections,acted solely at the mitochondrial electron transport chain(ETC)complex I,and that its association with IDH1 mutant inhibitor(IDH1^(m)i)AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro and in vivo.Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia(AML)patients using combinatory mitochondrial targeted medicines,particularly those who are resistant to or relapsing from IDH1m i.
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.
