Objectives To compare respiratory parameters of peripheral blood mononuclear cell mitochondria and iron metabolism indicators in patients with different NYHA functional classes of ischemic heart failure(HF).Methods Th...Objectives To compare respiratory parameters of peripheral blood mononuclear cell mitochondria and iron metabolism indicators in patients with different NYHA functional classes of ischemic heart failure(HF).Methods This single center, prospective, non-blinded study enrolled 20 patients with diagnosed chronic HF of ischemic genesis with reduced and mildly reduced left ventricle ejection fraction. The maximum oxygen consumption at the peak of the exercise test(VO2peak), iron metabolism parameters and respiratory activity of peripheral blood mononuclear cell mitochondria were assessed.Results Among the patients, a half of individuals were diagnosed with iron deficiency. Subgroups of patients with different HF severity did not significant differ in VO2peak(P=0.209), serum iron(P=0.468) and ferritin(P=0.235) levels. But there was a trend in increasing in these parameters with increasing NYHA HF functional class. Respiratory control coefficient(RC) in NADdependent and FAD-dependent mitochondrial oxidation were lower in patients with NYHA HF Ⅲ functional class compared to individuals with NYHA HF I functional class(P=0.028 and P=0.040, respectively). Serum iron(P=0.026), ferritin(P=0.045)levels, transferrin saturation(P=0.006) were negatively correlated with RC in NAD-dependent mitochondrial oxidation.Conclusions In aggravation of ischemic HF NYHA FC, there is a decrease in RC of PBMC mitochondria during the oxidation of NAD-dependent and FAD-dependent substrates. In the whole sample, patients with laboratory-confirmed iron deficiency accounted a half of the total number. Iron metabolism parameters had a paradoxical inverse relationship with the level of RC in PBMC mitochondria of patients with HF.展开更多
The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activator...The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.展开更多
AIM:To explore the role of a previously-found MYH9 tail domain mutation(p.E1384Q)in the pathogenesis of congenital cataract.METHODS:The cell experiments were conducted in vitro.Wild-type(WT)MYH9 and p.E1384Q mutant fr...AIM:To explore the role of a previously-found MYH9 tail domain mutation(p.E1384Q)in the pathogenesis of congenital cataract.METHODS:The cell experiments were conducted in vitro.Wild-type(WT)MYH9 and p.E1384Q mutant fragments were constructed,which was then transiently transfected into Hek293T cell lines.Western blotting and quantitative real time polymerase chain reaction(qRT-PCR)were used to analyze the protein and mRNA level of non-muscle myosin IIA(NM IIA)and F-actin in transfected cells,and fluorescence microscopy was applied to explore the subcellular localization of NM IIA and F-actin.Cell counting kit-8(CCK8),woundhealing and double staining flow cytometry assays were performed to evaluate the proliferation,migration and apoptosis function of transfected cells,respectively.Transmission electron microscope was conducted to observe the alteration of organelle structure.RESULTS:The transiently-transfected WT and p.E1384Q mutant Hek293T cell lines was constructed.Western blot demonstrated that,comparing with MYH9WT group,the relative protein amount of NM IIA and F-actin significantly decreased in MYH9E1384Q cells(P<0.001).qRT-PCR analysis revealed that the relative mRNA amount of NM IIA and F-actin also significantly reduced in MYH9E1384Q cells when compared with MYH9WT.The immunofluorescence microscopy showed that the fluorescence signal of NM IIA and F-actin significantly decreased in E1384Q cells.The diffuse cytoplasmic distribution of NM IIA in MYH9WT was changed to be clumped distribution,presenting a“speckled”pattern characterized by aggregates of small size in MYH9E1384Q.Functional study revealed that the E1384Q mutation significantly inhibited cell proliferation(P=0.003)and migration(P<0.001),and promoted apoptosis(P<0.001).Electron microscope showed that the mutation remarkably decreased the number of mitochondria(P<0.001)and changed the phenotype of mitochondria.CONCLUSION:The missense gene mutation in MYH9(p.E1384Q)causing congenital cataract results in decreased amount and altered subcellular distribution of NM IIA and F-actin,accompanied by decreased cell proliferation and migration,promotes apoptosis and mitochondrial alteration.展开更多
Objective To investigate the toxicity of cigarette smoke extract (CSE) and nicotine on mouse brain mitochondria as well as the protective effect of vitamin C in vitro. Method Mouse brain mitochondria in vitro was incu...Objective To investigate the toxicity of cigarette smoke extract (CSE) and nicotine on mouse brain mitochondria as well as the protective effect of vitamin C in vitro. Method Mouse brain mitochondria in vitro was incubated with CSE or nicotine in the absence or presence of vitamin C for 60 minutes, and the changes of mitochondrial function and structure were measured. Results CSE inhibited mitochondrial ATPase and cytochrome C oxidase activities in a dose-dependent manner. However, no significant changes in the peroxidation indices were observed when mitochondrial respiratory enzymes activity was inhibited, and protection of mitochondria from CSE-induced injury by vitamin C was not displayed in vitro. The effect of CSE on mouse brain mitochondria swelling response to calcium stimulation was dependent on calcium concentrations. CSE inhibited swelling of mitochondria at 6.5μmol/L Ca2+, but promoted swelling response at 250μmol/L Ca2+. Nicotine, the major component of cigarette smoke, showed no significant damage in mouse brain mitochondria in vitro. The CSE treatment induced mitochondrial inner membrane damage and vacuolization of the matrix, whereas the outer mitochondrial membrane appeared to be preserved. Conclusion The toxic effect of CSE on brain mitochondria may be due to its direct action on enzymatic activity rather than through oxygen free radical injury. Nicotine is not the responsible component for the toxicity of CSE to brain mitochondria.展开更多
Mammalian mitochondria are sensitive targets of cytotoxic effect of superoxide and nitric oxide (NO).In this study we measured mitochondrial state 3, 4 respiration, respiratory control rate (RCR) and phosphor-oxygen r...Mammalian mitochondria are sensitive targets of cytotoxic effect of superoxide and nitric oxide (NO).In this study we measured mitochondrial state 3, 4 respiration, respiratory control rate (RCR) and phosphor-oxygen ratio (P/O) to evaluate mitochondrial respiratory function (MRF) in cerebral ischemia and at 1, 3, 6, 24 and 48 h after reperfusion. We also observed the changes of MRF after giving N-nitro L- arginine (LNA) at various times. MRF was inhibited 30 min after cerebral ischemia. The major change was decrease in RCR, especially in the case of state 3 respiration. In the early stage of reperfusion, MRF recovered and state 3 was higher than the level of normal control. In later stage of reperfusion (at 6 h), obvious increase in state 4 led to decrease in RCR again. RCR was higher than that of reperfusion control by decreasing of state 4 when LNA was given at 1 h after reperfusion and 5 h thereafter; there were no change in MRF when LNA was given at the beginning of reperfusion. We concluded that MRF was further damaged, and ineffective oxygen consumption increased after reperfusion; LNA could protect MRF after reperfusion. Overproduction of endogenous NO has pathologic toxicity to mitochondria at 1- 2 h after reperfusion.展开更多
Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic ac...Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic activity and clinical application value.Herein,this work was conducted to investigate the protective effect of Pleurotus tuber-regium polysaccharide-protein complex funtionnalized SeNPs(PTR-SeNPs)against acetaminophen(APAP)-induced oxidative injure in HepG2 cells and C57BL/6J mouse liver.Further elucidation of the underlying molecular mechanism,in particular their modulation of Nrf2 signaling pathway was also performed.The results showed that PTR-SeNPs could significantly ameliorate APAP-induced oxidative injury as evidenced by a range of biochemical analysis,histopathological examination and immunoblotting study.PTR-SeNPs could hosphorylate and activate PKCδ,depress Keap1,and increase nuclear accumulation of Nrf2,resulting in upregulation of GCLC,GCLM,HO-1 and NQO-1 expression.Besides,PTR-SeNPs suppressed the biotransformation of APAP to generate intracellular ROS through CYP 2E1 inhibition,restoring the mitochondrial morphology.Furthermore,the protective effect of PTR-SeNPs against APAP induced hepatotoxicity was weakened as Nrf2 was depleted in vivo,indicating the pivotal role of Nrf2 signaling pathway in PTR-SeNPs mediated hepatoprotective efficacy.Being a potential hepatic protectant,PTR-SeNPs could serve as a new source of selenium supplement for health-promoting and biomedical applications.展开更多
Mitochondrial network architecture,which is closely related to mitochondrial function,is mechanically sensitive and regulated by multiple stimuli.However,the effects of microtopographic cues on mitochondria remain poo...Mitochondrial network architecture,which is closely related to mitochondrial function,is mechanically sensitive and regulated by multiple stimuli.However,the effects of microtopographic cues on mitochondria remain poorly defined.Herein,polycaprolactone(PCL)surfaces were used as models to investigate how micropatterns regulate mitochondrial network architecture and function in rat adipose-derived stem cells(rASCs).It was found that large pit(LP)-induced rASCs to form larger and more complex mitochondrial networks.Consistently,the expression of key genes related to mitochondrial dynamics revealed that mitochondrial fusion(MFN1 and MFN2)and midzone fission(DRP1 and MFF)were increased in rASCs on LP.In contrast,the middle pit(MP)-enhanced mitochondrial biogenesis,as evidenced by the larger mitochondrial area and higher expression of PGC-1.Both LP and MP promoted ATP production in rASCs.It is likely that LP increased ATP levels through modulating mitochondrial network architecture while MP stimulated mitochondria biogenesis to do so.Our study clarified the regulation of micropatterned surfaces on mitochondria,highlighting the potential of LP and MP as a simple platform to stimulate mitochondria and the subsequent cellular function of MSCs.展开更多
Andean potatoes(Solanum tuberosum ssp.andigena)are a good source of dietary polyphenols,such as phenolic acid and flavonoids.These polyphenols have several beneficial effects on human health due to their antioxidant p...Andean potatoes(Solanum tuberosum ssp.andigena)are a good source of dietary polyphenols,such as phenolic acid and flavonoids.These polyphenols have several beneficial effects on human health due to their antioxidant properties.Previously,we demonstrated that polyphenol extracts from Andean potato tubers exerted a concentration-dependent cytotoxic effect in human neuroblastoma cells.However,the mechanisms involved in this cytotoxic activity were not explored.Here,we show that polyphenols from Santa María tuber activated programmed cell death by caspase-independent apoptosis.They induced cell morphology changes,including the nucleus,and slightly affected the cell cycle.Furthermore,tuber polyphenols altered redox homeostasis and mitochondrial function of neuroblastoma cells,which increased the number of apoptotic cells.We also showed that neither Bcl-2 nor caspase-3 was involved in this mechanism of death.In summary,our results demonstrated that polyphenols from Santa María tuber are bioactive compounds that have mitochondria as a target and contribute to revalorizing Andean potatoes as a functional food.These findings suggest that they would be a good source of anti-tumor compounds that could induce tumor cell death even in apoptotic-resistant tumors,opening new therapeutic avenues.展开更多
Leber’s hereditary optic neuropathy(LHON)is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I,which is an important contributor to blindness among young adults across the globe.H...Leber’s hereditary optic neuropathy(LHON)is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I,which is an important contributor to blindness among young adults across the globe.However,the disorder has no available cures,since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them.Herein,PARKIN mRNA-loaded nanoparticle(mNP)-engineered mitochondria(mNP-Mito)were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria,normalizing the function of complex I for treating LHON.The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer,along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process.In a mouse model induced with a complex I inhibitor(rotenone,Rot),mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity(76.5%)compared to the group exposed to Rot damage(29.5%),which greatly promoted the restoration of ATP generation and mitiga-tion of ocular mitochondrial disease-related phenotypes.This study highlights the significance of nanoen-gineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.展开更多
基金supported by Russian Science Foundation,RSF 23-75-00009(part of the study corresponding to finding 1)Part of the study corresponding to finding 2 was carried out within the state assignment,FSR No.:122020300045-5(03.02.2022).
文摘Objectives To compare respiratory parameters of peripheral blood mononuclear cell mitochondria and iron metabolism indicators in patients with different NYHA functional classes of ischemic heart failure(HF).Methods This single center, prospective, non-blinded study enrolled 20 patients with diagnosed chronic HF of ischemic genesis with reduced and mildly reduced left ventricle ejection fraction. The maximum oxygen consumption at the peak of the exercise test(VO2peak), iron metabolism parameters and respiratory activity of peripheral blood mononuclear cell mitochondria were assessed.Results Among the patients, a half of individuals were diagnosed with iron deficiency. Subgroups of patients with different HF severity did not significant differ in VO2peak(P=0.209), serum iron(P=0.468) and ferritin(P=0.235) levels. But there was a trend in increasing in these parameters with increasing NYHA HF functional class. Respiratory control coefficient(RC) in NADdependent and FAD-dependent mitochondrial oxidation were lower in patients with NYHA HF Ⅲ functional class compared to individuals with NYHA HF I functional class(P=0.028 and P=0.040, respectively). Serum iron(P=0.026), ferritin(P=0.045)levels, transferrin saturation(P=0.006) were negatively correlated with RC in NAD-dependent mitochondrial oxidation.Conclusions In aggravation of ischemic HF NYHA FC, there is a decrease in RC of PBMC mitochondria during the oxidation of NAD-dependent and FAD-dependent substrates. In the whole sample, patients with laboratory-confirmed iron deficiency accounted a half of the total number. Iron metabolism parameters had a paradoxical inverse relationship with the level of RC in PBMC mitochondria of patients with HF.
文摘The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.
基金Supported by Beijing Municipal Natural Science Foundation(No.7202229No.7242168)China Primary Health Care Foundation(No.MTP2022C025).
文摘AIM:To explore the role of a previously-found MYH9 tail domain mutation(p.E1384Q)in the pathogenesis of congenital cataract.METHODS:The cell experiments were conducted in vitro.Wild-type(WT)MYH9 and p.E1384Q mutant fragments were constructed,which was then transiently transfected into Hek293T cell lines.Western blotting and quantitative real time polymerase chain reaction(qRT-PCR)were used to analyze the protein and mRNA level of non-muscle myosin IIA(NM IIA)and F-actin in transfected cells,and fluorescence microscopy was applied to explore the subcellular localization of NM IIA and F-actin.Cell counting kit-8(CCK8),woundhealing and double staining flow cytometry assays were performed to evaluate the proliferation,migration and apoptosis function of transfected cells,respectively.Transmission electron microscope was conducted to observe the alteration of organelle structure.RESULTS:The transiently-transfected WT and p.E1384Q mutant Hek293T cell lines was constructed.Western blot demonstrated that,comparing with MYH9WT group,the relative protein amount of NM IIA and F-actin significantly decreased in MYH9E1384Q cells(P<0.001).qRT-PCR analysis revealed that the relative mRNA amount of NM IIA and F-actin also significantly reduced in MYH9E1384Q cells when compared with MYH9WT.The immunofluorescence microscopy showed that the fluorescence signal of NM IIA and F-actin significantly decreased in E1384Q cells.The diffuse cytoplasmic distribution of NM IIA in MYH9WT was changed to be clumped distribution,presenting a“speckled”pattern characterized by aggregates of small size in MYH9E1384Q.Functional study revealed that the E1384Q mutation significantly inhibited cell proliferation(P=0.003)and migration(P<0.001),and promoted apoptosis(P<0.001).Electron microscope showed that the mutation remarkably decreased the number of mitochondria(P<0.001)and changed the phenotype of mitochondria.CONCLUSION:The missense gene mutation in MYH9(p.E1384Q)causing congenital cataract results in decreased amount and altered subcellular distribution of NM IIA and F-actin,accompanied by decreased cell proliferation and migration,promotes apoptosis and mitochondrial alteration.
文摘Objective To investigate the toxicity of cigarette smoke extract (CSE) and nicotine on mouse brain mitochondria as well as the protective effect of vitamin C in vitro. Method Mouse brain mitochondria in vitro was incubated with CSE or nicotine in the absence or presence of vitamin C for 60 minutes, and the changes of mitochondrial function and structure were measured. Results CSE inhibited mitochondrial ATPase and cytochrome C oxidase activities in a dose-dependent manner. However, no significant changes in the peroxidation indices were observed when mitochondrial respiratory enzymes activity was inhibited, and protection of mitochondria from CSE-induced injury by vitamin C was not displayed in vitro. The effect of CSE on mouse brain mitochondria swelling response to calcium stimulation was dependent on calcium concentrations. CSE inhibited swelling of mitochondria at 6.5μmol/L Ca2+, but promoted swelling response at 250μmol/L Ca2+. Nicotine, the major component of cigarette smoke, showed no significant damage in mouse brain mitochondria in vitro. The CSE treatment induced mitochondrial inner membrane damage and vacuolization of the matrix, whereas the outer mitochondrial membrane appeared to be preserved. Conclusion The toxic effect of CSE on brain mitochondria may be due to its direct action on enzymatic activity rather than through oxygen free radical injury. Nicotine is not the responsible component for the toxicity of CSE to brain mitochondria.
文摘Mammalian mitochondria are sensitive targets of cytotoxic effect of superoxide and nitric oxide (NO).In this study we measured mitochondrial state 3, 4 respiration, respiratory control rate (RCR) and phosphor-oxygen ratio (P/O) to evaluate mitochondrial respiratory function (MRF) in cerebral ischemia and at 1, 3, 6, 24 and 48 h after reperfusion. We also observed the changes of MRF after giving N-nitro L- arginine (LNA) at various times. MRF was inhibited 30 min after cerebral ischemia. The major change was decrease in RCR, especially in the case of state 3 respiration. In the early stage of reperfusion, MRF recovered and state 3 was higher than the level of normal control. In later stage of reperfusion (at 6 h), obvious increase in state 4 led to decrease in RCR again. RCR was higher than that of reperfusion control by decreasing of state 4 when LNA was given at 1 h after reperfusion and 5 h thereafter; there were no change in MRF when LNA was given at the beginning of reperfusion. We concluded that MRF was further damaged, and ineffective oxygen consumption increased after reperfusion; LNA could protect MRF after reperfusion. Overproduction of endogenous NO has pathologic toxicity to mitochondria at 1- 2 h after reperfusion.
基金financially supported by National Natural Science Foundation of China(81700524)Natural Science Foundation of Fujian Province(2022J01866)from Fujian Provincial Department of Science and Technology+1 种基金Key Project of Fujian University of Traditional Chinese Medicine(X2021019)Collaborative Innovation and Platform Establishment Project of Department of Science and Technology of Guangdong Province(2019A050520003)。
文摘Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic activity and clinical application value.Herein,this work was conducted to investigate the protective effect of Pleurotus tuber-regium polysaccharide-protein complex funtionnalized SeNPs(PTR-SeNPs)against acetaminophen(APAP)-induced oxidative injure in HepG2 cells and C57BL/6J mouse liver.Further elucidation of the underlying molecular mechanism,in particular their modulation of Nrf2 signaling pathway was also performed.The results showed that PTR-SeNPs could significantly ameliorate APAP-induced oxidative injury as evidenced by a range of biochemical analysis,histopathological examination and immunoblotting study.PTR-SeNPs could hosphorylate and activate PKCδ,depress Keap1,and increase nuclear accumulation of Nrf2,resulting in upregulation of GCLC,GCLM,HO-1 and NQO-1 expression.Besides,PTR-SeNPs suppressed the biotransformation of APAP to generate intracellular ROS through CYP 2E1 inhibition,restoring the mitochondrial morphology.Furthermore,the protective effect of PTR-SeNPs against APAP induced hepatotoxicity was weakened as Nrf2 was depleted in vivo,indicating the pivotal role of Nrf2 signaling pathway in PTR-SeNPs mediated hepatoprotective efficacy.Being a potential hepatic protectant,PTR-SeNPs could serve as a new source of selenium supplement for health-promoting and biomedical applications.
基金supported by the National Natural Science Foundation of China(T2288101,31971266,82272152)Guangdong Basic and Applied Basic Research Foundation(2022A1515011925)+2 种基金National Key R&D Program of China(2021YFC2400700)Science and Technology Innovation Program of Guangdong Province Medical Products Administration(2022ZDZ11)Applied Basic Research Program of Guangzhou city of China(202201010040).
文摘Mitochondrial network architecture,which is closely related to mitochondrial function,is mechanically sensitive and regulated by multiple stimuli.However,the effects of microtopographic cues on mitochondria remain poorly defined.Herein,polycaprolactone(PCL)surfaces were used as models to investigate how micropatterns regulate mitochondrial network architecture and function in rat adipose-derived stem cells(rASCs).It was found that large pit(LP)-induced rASCs to form larger and more complex mitochondrial networks.Consistently,the expression of key genes related to mitochondrial dynamics revealed that mitochondrial fusion(MFN1 and MFN2)and midzone fission(DRP1 and MFF)were increased in rASCs on LP.In contrast,the middle pit(MP)-enhanced mitochondrial biogenesis,as evidenced by the larger mitochondrial area and higher expression of PGC-1.Both LP and MP promoted ATP production in rASCs.It is likely that LP increased ATP levels through modulating mitochondrial network architecture while MP stimulated mitochondria biogenesis to do so.Our study clarified the regulation of micropatterned surfaces on mitochondria,highlighting the potential of LP and MP as a simple platform to stimulate mitochondria and the subsequent cellular function of MSCs.
基金funding from Fondo para la Investigación Científica y Tecnologica(FONCyT)(PICT 2018-0221)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)(PIP 2015-0762)Universidad Nacional de Mar del Plata(UNMdP,EXA 814/17).
文摘Andean potatoes(Solanum tuberosum ssp.andigena)are a good source of dietary polyphenols,such as phenolic acid and flavonoids.These polyphenols have several beneficial effects on human health due to their antioxidant properties.Previously,we demonstrated that polyphenol extracts from Andean potato tubers exerted a concentration-dependent cytotoxic effect in human neuroblastoma cells.However,the mechanisms involved in this cytotoxic activity were not explored.Here,we show that polyphenols from Santa María tuber activated programmed cell death by caspase-independent apoptosis.They induced cell morphology changes,including the nucleus,and slightly affected the cell cycle.Furthermore,tuber polyphenols altered redox homeostasis and mitochondrial function of neuroblastoma cells,which increased the number of apoptotic cells.We also showed that neither Bcl-2 nor caspase-3 was involved in this mechanism of death.In summary,our results demonstrated that polyphenols from Santa María tuber are bioactive compounds that have mitochondria as a target and contribute to revalorizing Andean potatoes as a functional food.These findings suggest that they would be a good source of anti-tumor compounds that could induce tumor cell death even in apoptotic-resistant tumors,opening new therapeutic avenues.
基金supported by the National Natural Science Foundation of China(82020108029,82304416,82073398,82302367,China)supported by the Natural Science Foundation of Jiangsu Province(BK20231016,BK20231019,China)+5 种基金the China Postdoctoral Science Foundation(grant Number:2022M720173,China)Jiangsu Funding Program for Excellent Postdoctoral Talent(2023,China)the Fundamental Research Funds for the Central Universities(2632023GR20,China)State Key Laboratory of Natural Medicines China Pharmaceutical University(SKLNMZZ202021,China)Double First-class University Projects(CPU2018GY06,China)Double First-Rate construction plan of China Pharmaceutical University(CPU2022QZ18,China)。
文摘Leber’s hereditary optic neuropathy(LHON)is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I,which is an important contributor to blindness among young adults across the globe.However,the disorder has no available cures,since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them.Herein,PARKIN mRNA-loaded nanoparticle(mNP)-engineered mitochondria(mNP-Mito)were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria,normalizing the function of complex I for treating LHON.The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer,along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process.In a mouse model induced with a complex I inhibitor(rotenone,Rot),mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity(76.5%)compared to the group exposed to Rot damage(29.5%),which greatly promoted the restoration of ATP generation and mitiga-tion of ocular mitochondrial disease-related phenotypes.This study highlights the significance of nanoen-gineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
