Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative p...Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative phosphorylation,in this study,effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia-exposed rats in vitro were investigated to screen anti-hypoxic drugs.Rats were exposed to a low-pressure environment of 405.35 mm Hg(54.04 kPa)for 3 days to establish high-altitude hypoxic models.Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers(sinomenine,silymarin,glycyrrhizic acid,baicalin,quercetin,ginkgolide B,saffron,pipedne,ginsenoside Rgl and oxymatrine)for 5 minutes in vitro.Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method,respectively.Hypoxic exposure significantly decreased the state 3 respiratory rate,respiratory control rate and mitochondrial membrane potential,and significantly increased the state 4 respiratory rate.Treatment with saffron ginsenoside Rgl and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro,while ginsenoside Rgl,piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats.The Chinese herbal monomers saffron,ginsenoside Rgl piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro.展开更多
Distribution and activity of mitochondda are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphor...Distribution and activity of mitochondda are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5＇- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5＇-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by ＂second control mechanisms,＂ such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, aUosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5＇-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria similarly, decline of antioxidative enzyme activities （e.g. in the elderly） enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.展开更多
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
Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and...Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.展开更多
Thiols play very important role in the intracellular redox homeostasis. Imbalance in the redox status leads to changes in the intracellular metabolism including respiration. Thiol stress, a reductive type of stress ca...Thiols play very important role in the intracellular redox homeostasis. Imbalance in the redox status leads to changes in the intracellular metabolism including respiration. Thiol stress, a reductive type of stress can also cause redox imbalance. When Gram-positive bacterium Strep- tomyces coelicolor was exposed to thiol stress, catalaseA was induced. Induction of catalaseA is the consequence of elevation of ROS (reactive oxygen species). The two major sources of reactive oxygen species are Fenton reaction and slippage of electrons from electron transport chain during respiration. Hence, the effect of thiol stress was checked on the rate of oxidative phosphorylation in S. coelicolor. We found correlation in the increase of oxidative phosphorylation rate and the generation of ROS, subsequently leading to induction of catalase. It was observed that thiol stress does not affect the functionality of the individual complexes of the ETC, but still there was an increase in the overall respiration, which may lead to generation of more ROS leading to induction of catalase.展开更多
Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 g...Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.展开更多
OBJECTIVE To probe into the anti-esophagus cancer activity and mechanisms of DN3,a novel natural diterpenoid derivative.METHODS The anti-tumor activity in vitro of DN3 was evaluated by MTT,and by using human esophagea...OBJECTIVE To probe into the anti-esophagus cancer activity and mechanisms of DN3,a novel natural diterpenoid derivative.METHODS The anti-tumor activity in vitro of DN3 was evaluated by MTT,and by using human esophageal carcinoma cells xenografted into athymic mice model in vivo.The specific mechanisms of DN3,as a dual inhibitor of glycolysis and oxidative phos.phorylation(OXPHOS) were explored through cell and molecular biology techniques.For instance,the manner of cancer cell death induced by DN3 was characterized by hoechst33342,FITC-Annexin V/PI staining and flow cytometric analysis,then these changes of glucose consumption,glucose uptake and lactate production in glycolysis,as well as oxygen consumption rate(OCR) and ATP content in OXPHOS caused by DN3 were performed separately through related kits and SeahorseBioscience XF24 Extra.cellular Flux Analyzer.Furthermore,in order to obtain a clear understanding of the inhibition of DN3 to glycolysis and OXPHOS,these regulatory factors were investigated by Western blot,such as PI3K/AKT,c-Myc and p53 of glycolysis,Bax and HK2 of mitochondrial function.RESULTS DN3 inhibited the growth of esophagus cancer cell EC9706,EC109 and EC1 cells in a dose and time dependent manner,but showed no significant effects on human esophageal epithelial cells(HEECs).DN3 caused significant G2/M arrest of esophagus cancer cell lines and induced apoptosis of these cell lines,which indicated DN3 inhibited the growth of esophagus cancer cell through blocking cell cycle and inducing apoptosis in a dose and time-dependent manner.Importantly,8 μM DN3 decreased the extracellular acidification rate(ECAR) by 45% in EC109,which indicated glycolysis was inhibited by DN3.Mean.while,DN3 decreased the oxygen consumption rate(OCR) and the OCR linked to intracellular ATP production in EC109 cells,but that was not obvious in HEECs,so which indicated that DN3 could selec.tively block OXPHOS of cancer cells.In addition,the accumulation of reactive oxygen species(ROS)and the drop of mitochondrial membrane potential(MMP) were also observed in EC109 incubated by DN3,which suggested mitochondrial biological function was disturbed.Furthermore,the expression of PI3K/AKT,c-Myc and HK2 related to glycolysis were down-regulated by DN3,but the p53 and Bax were up-regulated in esophageal carcinoma cells.The changes of these enzymes accounted for the decreased glycolysisand OXPHOS in esophageal carcinoma cells treated by DN3.CONCLUSION The new compound DN3 has a strong anti-esophageal carcinoma activity,and it is tolerable that DN3 is seen as a dual inhibitor of glycolysis and oxidative phosphorylation.展开更多
3-hydroxy-3-methylgulutaryl-coenzyme A （HMG-CoA） reductase inhibitors or statins are a kind of lipid-lowering agents and have been used for the prevention and treatment of Cardiovascular diseases. Recent studies sug...3-hydroxy-3-methylgulutaryl-coenzyme A （HMG-CoA） reductase inhibitors or statins are a kind of lipid-lowering agents and have been used for the prevention and treatment of Cardiovascular diseases. Recent studies suggested that statins, besides lowering cholesterol, may protect vessels by enhancing the activity of endothelial nitric oxide synthase （eNOS）. In the present study, we investigated if simvastatin increases eNOS activity through its phosphorylation in 293 cells （293-eNOS） with stable expression of eNOS. The results showed that incubation of 293-eNOS cells with simvastatin （10 μm/L） for 2 h significantly increased in the activity of eNOS as shown by the conversion of L-arginine to L-citrulline （2889.70±201.51 versus 5630.18＋218.75 pmol/min . mg proteins） （P〈0.01）. Western blotting revealed that simvastatin increased phosphorylation of eNOS at 1177 （ser） and also 495 （thr） but did not affect the overall expression of eNOS or inducible NOS. Further study found that simvastatin raised phosphorylation levels of Akt and AMPK, and such effect could be antagonized by Akt inhibitor or AMPK inhibitor. These results suggest that simvastatin could stimulate,the activity of eNOS via its phosphorylation by Akt and AMPK, which provides a new mechanism, other than lipid-lowering effect, for the cardiovascular protection of statins.展开更多
Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s di...Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease(PD)in zebrafish.Methods:In the current study,zebrafish were treated with CBL at doses of 1.25,2.5,and 5 mL/kg body weight for 7 consecutive days.MPTP(20 mg/kg body weight)was administered on alternative days-1st,3rd,5th,and 7th.On day 7,zebrafish were sacrificed,and their brains were isolated for biochemical,neurochemical,histopathological,IHC,and neurotransmitter analysis.Results:The treatment with CBL significantly increased total distance traveled and the number of entries in the top zone,which was impaired by MPTP.CBL treatment significantly restored the level of glutathione,superoxide dismutase,and catalase while reducing malondialdehyde level.It also reduced the level of pro-inflammatory mediators interleukin-1β,interleukin-6,and tumor necrosis factor-αin the MPTP-induced PD in the zebrafish model.In histopathological evaluation,pyknotic cells and signs of inflammation were significantly reduced in CBL-treated groups.A significant dose-dependent reduction in glutamate,along with elevations in dopamine,gamma-aminobutyric acid,serotonin,and noradrenaline,was observed in zebrafish treated with CBL.An immunohistochemistry analysis demonstrated that Akt was phosphorylated promptly by CBL,which was downregulated in MPTP-induced PD in zebrafish.Conclusions:These findings suggest that CBL exerts a neuroprotective effect through activation of Akt and may hold therapeutic potential for the treatment of this devastating neurological condition.展开更多
Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidati...Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.展开更多
The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are...The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are characterized by increased levels of mitochondrial complexesⅠ,Ⅱ,and Ⅳ followed by increased superoxide anion generation.Moreover,As（V） triggers an apoptotic mode of cell death,demonstrated by an apoptotic SubG1 peak,associated with an alteration of plasma membrane integrity.There is also a decrease in transmembrane mitochondrial potential and mitochondrial adenosine triphosphate ATP.It is therefore tempting to speculate that As（V） triggers mitochondrial dysfunction,which may lead to defective oxidative phosphorylation subsequently causing mitochondrial oxidative damage,which in turn induces an apoptotic mode of cell death.展开更多
To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we establishe...To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we established an in vitro transfection of human HO-1 gene into rat VSMC mediated by a retroviral vector. The results showed that the profound expression of HO-1 protein as well as HO activity was 1.8- and 2.0-fold increased respectively in the transfected cells compared to the non-transfected ones. The treatment of VSMC with different concentrations of H2O2 led to the remarkable cell damage as indicated by survival rate and LDH leakage. However, the resistance of the HO-1 transfected VSMC against H2O2 was significantly raised. This protective effect was dramatically diminished when the transfected VSMC were pretreated with ZnPP-IX, a specific inhibitor of HO, for 24 h. In addition, we found that the growth potential of the transfected cells was significantly inhibited directly by increased activity of HO-1, and this effect might be related to decreased phosphorylation of MAPK. These results suggest that the overexpression of introduced hHO-1 is potentially able to reduce the risk factors of atherosclerosis, partially due to its cellular protection against oxidative injury and to its inhibitory effect on cellular proliferation.展开更多
Cotyledon mitochondrion respiration and oxidative phosphorylation activity were studied in two groups of soybean seeds. One group was primed with polyethylene glycol (PEG) for different periods of time, and the other ...Cotyledon mitochondrion respiration and oxidative phosphorylation activity were studied in two groups of soybean seeds. One group was primed with polyethylene glycol (PEG) for different periods of time, and the other was unprimed (control), and both were then exposed to imbibition at low temperatures before their germination. The results indicated that when L-Malate (L-Mal) and á-Ketoglutarate (α-Kg) were used as substrates, the ADP-stimulated mitochondria respiration rates of control seeds were mark- edly higher than state Ⅲ respiration rates of primed seeds. However, the osmoconditioning pretreatment significantly enhanced the oxidative phosphorylation activity of cotyledon mitochondrion in 12 h. The oxidative phosphorylation activity of the mitochondrion of primed seeds was normal and the ADP/O value was consistent with the theoretical one. When reduced nicotinamide adenine dinu- cleotide (NADH) was used as the substrate, the mitochondria of control seeds still had oxidative phosphorylation activity, while ADP/O value was obviously lower than that of mitochondria of primed seeds. When Succinate (Succ) was used as the substrate, the oxidative phosphorylation activity of the primed seeds was normal after priming for 24 h. When different substrates were used, the emerging order of the oxidative phosphorylation activity of the primed seeds was NADH, α-Kg, Succ and in the last place L-Mal. The mechanism of soybean imbibitionl chilling injury and protective effect of PEG priming were discussed.展开更多
Male infertility has become a global concern,accounting for 20-70%of infertility.Dysfunctional spermatogenesis is the most common cause of male infertility;thus,treating abnormal spermatogenesis may improve male infer...Male infertility has become a global concern,accounting for 20-70%of infertility.Dysfunctional spermatogenesis is the most common cause of male infertility;thus,treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community.Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways,such as mitochondrial oxidative phosphorylation(OXPHOS).Mitochondrial OXPHOS transmits electrons through the respiratory chain,synthesizes adenosine triphosphate(ATP),and produces reactive oxygen species(ROS).These mechanisms are vital for spermatogenesis,especially to maintain the normal function of testicular Sertoli cells and germ cells.The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply,oxidative stress,apoptosis,or ferroptosis,all inhibiting spermatogenesis and damaging the male reproductive system,leading to male infertility.This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells,which disrupts spermatogenesis and results in male infertility.In addition,we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders.However,relevant treatments have not been fully elucidated.Therefore,targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention.We believe this review will provide new and more accurate ideas for treating male infertility.展开更多
Exosomes as bilayer membranous vesicles are abundant in seminal plasma and mediate intercellular communication by transferring active biomolecules.Numerous studies have revealed the involvement of exosomes in regulati...Exosomes as bilayer membranous vesicles are abundant in seminal plasma and mediate intercellular communication by transferring active biomolecules.Numerous studies have revealed the involvement of exosomes in regulating various biological properties of spermatozoa.However,the beneficial roles of seminal plasma exosomes in maintaining spermatozoon motility and mitochondrial function during liquid storage have not yet been unexplored in goat.In this study,the reduction of ATP content in goat spermatozoa was detected along with the decrease in spermatozoon motility under liquid storage,and the level of oxidative phosphorylation was also decreased.The interaction of exosomes and spermatozoon mitochondria was observed using high pressure freezing/freezesubstitution in combination with transmission electron microscope.Seminal plasma exosomes of goat were isolated and used to incubate with spermatozoa,and the binding and fusing of exosomes with spermatozoa was further validated.Furthermore,the addition of seminal plasma exosomes exhibited an increase in motility and oxidative phosphorylation in liquid-stored spermatozoa.Several mitochondrial functional parameters,including mitochondrial membrane potential,the levels of mitochondrial ROS and intracellular Ca^(2+),and the copy number and integrity of mitochondrial DNA,were also improved in spermatozoa after incubating with exosomes.Notably,the level of TFAM protein was increased in exosome-treated spermatozoa,indicating that the enhanced proteins may be delivered by exosomes to spermatozoa.These results suggest that seminal plasma exosomes could improve spermatozoon motility and mitochondrial function by regulating oxidative phosphorylation,which would provide insights into the understanding of protective roles of exosomes in goat spermatozoa during liquid storage.展开更多
The light-driven water-splitting reaction of photosystem II exposes its key reaction center core protein subunits to irreversible oxidative photodamage.A rapid repair cycle replaces the photodamaged core subunits in p...The light-driven water-splitting reaction of photosystem II exposes its key reaction center core protein subunits to irreversible oxidative photodamage.A rapid repair cycle replaces the photodamaged core subunits in plants,but how the large antenna-core supercomplex structures of plant photosystem II disassemble for repair is not currently understood.Here,we report the specific involvement of phosphorylation in removal of the peripheral antenna from the core and monomerization of the dimeric cores.However,monomeric cores disassemble further into smaller subcomplexes,even in the absence of phosphorylation,suggesting that there are other unknown mechanisms of disassembly.In this regard,we show that oxidative modifications of amino acids in core protein subunits of photosystem II are active mediators of monomeric core disassembly.Oxidative modifications thus likely disassemble only the damagedmonomeric cores,ensuring an economical photosystem disassembly process.Taken together,our results suggest that phosphorylation and oxidative modification play distinct roles in photosystem II disassembly and repair.展开更多
Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest...Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest in AML chemoresistance.In this study,we identified mitochondrial DNA content(mtDNAc),measured by quantitative PCR,as a simple and precise marker to stratify the metabolic states of AML patients.We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation(OXPHOS),often correlating with chemoresistance.Clinically,patients receiving cytarabine and an anthracycline-based regimen(7+3 regimen)experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence.展开更多
线粒体电子传递链(Electron transport chain,ETC)通过四个酶复合体将电子从还原供体传递到氧气,同时驱动质子跨内膜转运,形成质子梯度,F1F0 ATP合酶利用该梯度合成ATP,完成细胞能量转换。在此过程中,有少量电子泄漏出ETC从而产生了活性...线粒体电子传递链(Electron transport chain,ETC)通过四个酶复合体将电子从还原供体传递到氧气,同时驱动质子跨内膜转运,形成质子梯度,F1F0 ATP合酶利用该梯度合成ATP,完成细胞能量转换。在此过程中,有少量电子泄漏出ETC从而产生了活性氧(Reactive oxygen species,ROS)。ROS在干细胞的增殖、分化及自我更新中发挥着重要的生理作用,因此ROS水平的精确调控对干细胞的稳态与功能至关重要。研究ETC如何通过ROS的生成来调控干细胞的命运,对于深入理解干细胞的调控机制具有重要意义。本文围绕ETC复合体的结构功能、线粒体ROS产生及其调控干细胞命运机制进行综述,探讨该机制不仅为氧自由基研究提供了新视角,也为临床治疗肿瘤、衰老、神经退行性疾病以及干细胞功能相关疾病提供潜在的治疗靶点。展开更多
A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch betw...A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2: MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.展开更多
基金supported by the Natural Science Foundation of China,No.81171875
文摘Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative phosphorylation,in this study,effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia-exposed rats in vitro were investigated to screen anti-hypoxic drugs.Rats were exposed to a low-pressure environment of 405.35 mm Hg(54.04 kPa)for 3 days to establish high-altitude hypoxic models.Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers(sinomenine,silymarin,glycyrrhizic acid,baicalin,quercetin,ginkgolide B,saffron,pipedne,ginsenoside Rgl and oxymatrine)for 5 minutes in vitro.Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method,respectively.Hypoxic exposure significantly decreased the state 3 respiratory rate,respiratory control rate and mitochondrial membrane potential,and significantly increased the state 4 respiratory rate.Treatment with saffron ginsenoside Rgl and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro,while ginsenoside Rgl,piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats.The Chinese herbal monomers saffron,ginsenoside Rgl piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro.
基金supported by grant NoMSM0021620849 given by the Ministry of Education,Youth and Sports of the Czech Republicby project PRVOUK-P26/LF1/4given by Charles University in Prague+1 种基金by grant No. SVV-2012-264514 from Charles University in Pragueby grant No.41310 given by the Grant Agency of Charles University in Prague,Czech Republic
文摘Distribution and activity of mitochondda are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5＇- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5＇-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by ＂second control mechanisms,＂ such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, aUosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5＇-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria similarly, decline of antioxidative enzyme activities （e.g. in the elderly） enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.
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.
基金supported by grants from the National Natural Science Foundation of China(Nos.81960732 and 82060733)the Natural Science Foundation of Jiangxi Province(No.20224BAB206111)+2 种基金the Science and Technology Plan of Jiangxi Provincial Health Commission(No.202311141)the Open Project of Jiangxi Provincial Key Laboratory of Drug Design and Evaluation(No.JKLDE-KF-2101)the Open Project of Key Laboratory of Modern Preparation of TCM,Ministry of Education,Jiangxi University of Chinese Medicine(No.TCM-201911).
文摘Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.
文摘Thiols play very important role in the intracellular redox homeostasis. Imbalance in the redox status leads to changes in the intracellular metabolism including respiration. Thiol stress, a reductive type of stress can also cause redox imbalance. When Gram-positive bacterium Strep- tomyces coelicolor was exposed to thiol stress, catalaseA was induced. Induction of catalaseA is the consequence of elevation of ROS (reactive oxygen species). The two major sources of reactive oxygen species are Fenton reaction and slippage of electrons from electron transport chain during respiration. Hence, the effect of thiol stress was checked on the rate of oxidative phosphorylation in S. coelicolor. We found correlation in the increase of oxidative phosphorylation rate and the generation of ROS, subsequently leading to induction of catalase. It was observed that thiol stress does not affect the functionality of the individual complexes of the ETC, but still there was an increase in the overall respiration, which may lead to generation of more ROS leading to induction of catalase.
文摘Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.
基金supported by National Natural Science Foundation of China(81502952)
文摘OBJECTIVE To probe into the anti-esophagus cancer activity and mechanisms of DN3,a novel natural diterpenoid derivative.METHODS The anti-tumor activity in vitro of DN3 was evaluated by MTT,and by using human esophageal carcinoma cells xenografted into athymic mice model in vivo.The specific mechanisms of DN3,as a dual inhibitor of glycolysis and oxidative phos.phorylation(OXPHOS) were explored through cell and molecular biology techniques.For instance,the manner of cancer cell death induced by DN3 was characterized by hoechst33342,FITC-Annexin V/PI staining and flow cytometric analysis,then these changes of glucose consumption,glucose uptake and lactate production in glycolysis,as well as oxygen consumption rate(OCR) and ATP content in OXPHOS caused by DN3 were performed separately through related kits and SeahorseBioscience XF24 Extra.cellular Flux Analyzer.Furthermore,in order to obtain a clear understanding of the inhibition of DN3 to glycolysis and OXPHOS,these regulatory factors were investigated by Western blot,such as PI3K/AKT,c-Myc and p53 of glycolysis,Bax and HK2 of mitochondrial function.RESULTS DN3 inhibited the growth of esophagus cancer cell EC9706,EC109 and EC1 cells in a dose and time dependent manner,but showed no significant effects on human esophageal epithelial cells(HEECs).DN3 caused significant G2/M arrest of esophagus cancer cell lines and induced apoptosis of these cell lines,which indicated DN3 inhibited the growth of esophagus cancer cell through blocking cell cycle and inducing apoptosis in a dose and time-dependent manner.Importantly,8 μM DN3 decreased the extracellular acidification rate(ECAR) by 45% in EC109,which indicated glycolysis was inhibited by DN3.Mean.while,DN3 decreased the oxygen consumption rate(OCR) and the OCR linked to intracellular ATP production in EC109 cells,but that was not obvious in HEECs,so which indicated that DN3 could selec.tively block OXPHOS of cancer cells.In addition,the accumulation of reactive oxygen species(ROS)and the drop of mitochondrial membrane potential(MMP) were also observed in EC109 incubated by DN3,which suggested mitochondrial biological function was disturbed.Furthermore,the expression of PI3K/AKT,c-Myc and HK2 related to glycolysis were down-regulated by DN3,but the p53 and Bax were up-regulated in esophageal carcinoma cells.The changes of these enzymes accounted for the decreased glycolysisand OXPHOS in esophageal carcinoma cells treated by DN3.CONCLUSION The new compound DN3 has a strong anti-esophageal carcinoma activity,and it is tolerable that DN3 is seen as a dual inhibitor of glycolysis and oxidative phosphorylation.
基金supported by grants from National Natural Sciences Foundation of China (No. 30430320 and 30770882)National 973 Project (No. 2007CB512004)
文摘3-hydroxy-3-methylgulutaryl-coenzyme A （HMG-CoA） reductase inhibitors or statins are a kind of lipid-lowering agents and have been used for the prevention and treatment of Cardiovascular diseases. Recent studies suggested that statins, besides lowering cholesterol, may protect vessels by enhancing the activity of endothelial nitric oxide synthase （eNOS）. In the present study, we investigated if simvastatin increases eNOS activity through its phosphorylation in 293 cells （293-eNOS） with stable expression of eNOS. The results showed that incubation of 293-eNOS cells with simvastatin （10 μm/L） for 2 h significantly increased in the activity of eNOS as shown by the conversion of L-arginine to L-citrulline （2889.70±201.51 versus 5630.18＋218.75 pmol/min . mg proteins） （P〈0.01）. Western blotting revealed that simvastatin increased phosphorylation of eNOS at 1177 （ser） and also 495 （thr） but did not affect the overall expression of eNOS or inducible NOS. Further study found that simvastatin raised phosphorylation levels of Akt and AMPK, and such effect could be antagonized by Akt inhibitor or AMPK inhibitor. These results suggest that simvastatin could stimulate,the activity of eNOS via its phosphorylation by Akt and AMPK, which provides a new mechanism, other than lipid-lowering effect, for the cardiovascular protection of statins.
基金funded by ICMR,New Delhi(Grant No.45/29/2022-PHA/BMS).
文摘Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease(PD)in zebrafish.Methods:In the current study,zebrafish were treated with CBL at doses of 1.25,2.5,and 5 mL/kg body weight for 7 consecutive days.MPTP(20 mg/kg body weight)was administered on alternative days-1st,3rd,5th,and 7th.On day 7,zebrafish were sacrificed,and their brains were isolated for biochemical,neurochemical,histopathological,IHC,and neurotransmitter analysis.Results:The treatment with CBL significantly increased total distance traveled and the number of entries in the top zone,which was impaired by MPTP.CBL treatment significantly restored the level of glutathione,superoxide dismutase,and catalase while reducing malondialdehyde level.It also reduced the level of pro-inflammatory mediators interleukin-1β,interleukin-6,and tumor necrosis factor-αin the MPTP-induced PD in the zebrafish model.In histopathological evaluation,pyknotic cells and signs of inflammation were significantly reduced in CBL-treated groups.A significant dose-dependent reduction in glutamate,along with elevations in dopamine,gamma-aminobutyric acid,serotonin,and noradrenaline,was observed in zebrafish treated with CBL.An immunohistochemistry analysis demonstrated that Akt was phosphorylated promptly by CBL,which was downregulated in MPTP-induced PD in zebrafish.Conclusions:These findings suggest that CBL exerts a neuroprotective effect through activation of Akt and may hold therapeutic potential for the treatment of this devastating neurological condition.
文摘Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.
基金supported by grants from the University of Bourgogne(Dijon,France)the University of Monastir(Monastir,Tunisia)
文摘The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are characterized by increased levels of mitochondrial complexesⅠ,Ⅱ,and Ⅳ followed by increased superoxide anion generation.Moreover,As（V） triggers an apoptotic mode of cell death,demonstrated by an apoptotic SubG1 peak,associated with an alteration of plasma membrane integrity.There is also a decrease in transmembrane mitochondrial potential and mitochondrial adenosine triphosphate ATP.It is therefore tempting to speculate that As（V） triggers mitochondrial dysfunction,which may lead to defective oxidative phosphorylation subsequently causing mitochondrial oxidative damage,which in turn induces an apoptotic mode of cell death.
基金This work was kindly supported by Na-tional Natural Science Foundation of China(No.39670308)
文摘To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we established an in vitro transfection of human HO-1 gene into rat VSMC mediated by a retroviral vector. The results showed that the profound expression of HO-1 protein as well as HO activity was 1.8- and 2.0-fold increased respectively in the transfected cells compared to the non-transfected ones. The treatment of VSMC with different concentrations of H2O2 led to the remarkable cell damage as indicated by survival rate and LDH leakage. However, the resistance of the HO-1 transfected VSMC against H2O2 was significantly raised. This protective effect was dramatically diminished when the transfected VSMC were pretreated with ZnPP-IX, a specific inhibitor of HO, for 24 h. In addition, we found that the growth potential of the transfected cells was significantly inhibited directly by increased activity of HO-1, and this effect might be related to decreased phosphorylation of MAPK. These results suggest that the overexpression of introduced hHO-1 is potentially able to reduce the risk factors of atherosclerosis, partially due to its cellular protection against oxidative injury and to its inhibitory effect on cellular proliferation.
基金the National Natural Science Foundation of China (Grant No.30170100)
文摘Cotyledon mitochondrion respiration and oxidative phosphorylation activity were studied in two groups of soybean seeds. One group was primed with polyethylene glycol (PEG) for different periods of time, and the other was unprimed (control), and both were then exposed to imbibition at low temperatures before their germination. The results indicated that when L-Malate (L-Mal) and á-Ketoglutarate (α-Kg) were used as substrates, the ADP-stimulated mitochondria respiration rates of control seeds were mark- edly higher than state Ⅲ respiration rates of primed seeds. However, the osmoconditioning pretreatment significantly enhanced the oxidative phosphorylation activity of cotyledon mitochondrion in 12 h. The oxidative phosphorylation activity of the mitochondrion of primed seeds was normal and the ADP/O value was consistent with the theoretical one. When reduced nicotinamide adenine dinu- cleotide (NADH) was used as the substrate, the mitochondria of control seeds still had oxidative phosphorylation activity, while ADP/O value was obviously lower than that of mitochondria of primed seeds. When Succinate (Succ) was used as the substrate, the oxidative phosphorylation activity of the primed seeds was normal after priming for 24 h. When different substrates were used, the emerging order of the oxidative phosphorylation activity of the primed seeds was NADH, α-Kg, Succ and in the last place L-Mal. The mechanism of soybean imbibitionl chilling injury and protective effect of PEG priming were discussed.
基金supported by fundings from the Research Start-up Fund of Jining Medical University(Nos.600791001 and 600980001)Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation in Jining Medical University(No.JYHL2021MS13)the National Natural Science Foundation of China(No.81700055).
文摘Male infertility has become a global concern,accounting for 20-70%of infertility.Dysfunctional spermatogenesis is the most common cause of male infertility;thus,treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community.Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways,such as mitochondrial oxidative phosphorylation(OXPHOS).Mitochondrial OXPHOS transmits electrons through the respiratory chain,synthesizes adenosine triphosphate(ATP),and produces reactive oxygen species(ROS).These mechanisms are vital for spermatogenesis,especially to maintain the normal function of testicular Sertoli cells and germ cells.The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply,oxidative stress,apoptosis,or ferroptosis,all inhibiting spermatogenesis and damaging the male reproductive system,leading to male infertility.This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells,which disrupts spermatogenesis and results in male infertility.In addition,we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders.However,relevant treatments have not been fully elucidated.Therefore,targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention.We believe this review will provide new and more accurate ideas for treating male infertility.
基金supported by the National Natural Science Foundation of China(31902223).
文摘Exosomes as bilayer membranous vesicles are abundant in seminal plasma and mediate intercellular communication by transferring active biomolecules.Numerous studies have revealed the involvement of exosomes in regulating various biological properties of spermatozoa.However,the beneficial roles of seminal plasma exosomes in maintaining spermatozoon motility and mitochondrial function during liquid storage have not yet been unexplored in goat.In this study,the reduction of ATP content in goat spermatozoa was detected along with the decrease in spermatozoon motility under liquid storage,and the level of oxidative phosphorylation was also decreased.The interaction of exosomes and spermatozoon mitochondria was observed using high pressure freezing/freezesubstitution in combination with transmission electron microscope.Seminal plasma exosomes of goat were isolated and used to incubate with spermatozoa,and the binding and fusing of exosomes with spermatozoa was further validated.Furthermore,the addition of seminal plasma exosomes exhibited an increase in motility and oxidative phosphorylation in liquid-stored spermatozoa.Several mitochondrial functional parameters,including mitochondrial membrane potential,the levels of mitochondrial ROS and intracellular Ca^(2+),and the copy number and integrity of mitochondrial DNA,were also improved in spermatozoa after incubating with exosomes.Notably,the level of TFAM protein was increased in exosome-treated spermatozoa,indicating that the enhanced proteins may be delivered by exosomes to spermatozoa.These results suggest that seminal plasma exosomes could improve spermatozoon motility and mitochondrial function by regulating oxidative phosphorylation,which would provide insights into the understanding of protective roles of exosomes in goat spermatozoa during liquid storage.
基金supported by grants to S.P.from the United States Department of Energy(DOE)(DE-SC0020639)the United States Department of Agriculture-National Institute of Food and Agriculture(USDA-NIFA)(Hatch:1013608)S.D.M.acknowledges USDA-NIFA for an EWD predoctoral fellowship(2021-67034-35183).
文摘The light-driven water-splitting reaction of photosystem II exposes its key reaction center core protein subunits to irreversible oxidative photodamage.A rapid repair cycle replaces the photodamaged core subunits in plants,but how the large antenna-core supercomplex structures of plant photosystem II disassemble for repair is not currently understood.Here,we report the specific involvement of phosphorylation in removal of the peripheral antenna from the core and monomerization of the dimeric cores.However,monomeric cores disassemble further into smaller subcomplexes,even in the absence of phosphorylation,suggesting that there are other unknown mechanisms of disassembly.In this regard,we show that oxidative modifications of amino acids in core protein subunits of photosystem II are active mediators of monomeric core disassembly.Oxidative modifications thus likely disassemble only the damagedmonomeric cores,ensuring an economical photosystem disassembly process.Taken together,our results suggest that phosphorylation and oxidative modification play distinct roles in photosystem II disassembly and repair.
基金supported by Fundação de AmparoàPesquisa do Estado de São Paulo(FAPESP,Grant#2013/08135-2,CNPq:465539/2014-9)D.A.P-M.Received a fellowship from FAPESP(Grant#2017/23117-1)+2 种基金I.W.received a fellowship from FAPESP(Grant#2015/09228-0)L.Q.and P.C.were funded by UKRI/MRC grant#MR/R007608/1.A.R.L-A.Received a research grant and fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,Grant#303479/2018-3,#405918/2022-4)I.W and D.A.P-M were sponsored by the Abel Tasman Talent Program(ATTP)of the Graduate School of Medical Sciences of the University of Groningen/University Medical Center Groningen(UG/UMCG),The Netherlands.
文摘Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest in AML chemoresistance.In this study,we identified mitochondrial DNA content(mtDNAc),measured by quantitative PCR,as a simple and precise marker to stratify the metabolic states of AML patients.We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation(OXPHOS),often correlating with chemoresistance.Clinically,patients receiving cytarabine and an anthracycline-based regimen(7+3 regimen)experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence.
基金Ministry of Science and Technology of the People's Republic of China (2017YFA0503404 and 2016YFC1304803)the National Natural Science Foundation of China (Grant Nos. 31625014, 31621063 and 31830040).
文摘A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2: MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.
