Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidati...Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2＋ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative diseases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.展开更多
Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,t...Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,展开更多
BACKGROUND The functions of infiltrating CD8^(+)T cells are often impaired due to tumor cells causing nutrient deprivation in the tumor microenvironment.Thus,the mechanisms of CD8^(+)T cell dysfunction have become a h...BACKGROUND The functions of infiltrating CD8^(+)T cells are often impaired due to tumor cells causing nutrient deprivation in the tumor microenvironment.Thus,the mechanisms of CD8^(+)T cell dysfunction have become a hot research topic,and there is increased interest on how changes in metabolomics correlate with CD8^(+)T cell dysfunction.AIM To investigate whether and how glutamine metabolism affects the function of infiltrating CD8^(+)T cells in hepatocellular carcinoma.METHODS Immunohistochemical staining and immunofluorescence were performed on surgically resected liver tissues from patients.Differentially expressed genes in infiltrating CD8^(+)T cells in hepatocellular carcinoma were detected using RNA sequencing.Activated CD8^(+)T cells were co-cultured with Huh-7 cells for 3 d.The function and mitochondrial status of CD8^(+)T cells were analyzed by flow cytometry,quantitative real-time polymerase chain reaction,and transmission electron microscopy.Next,CD8^(+)T cells were treated with the mitochondrial protective and damaging agents.Functional alterations in CD8^(+)T cells were detected by flow cytometry.Then,complete medium without glutamine was used to culture cells and their functional changes and mitochondrial status were detected.RESULTS There were a large number of infiltrating PD-1+CD8^(+)T cells in liver cancer tissues.Next,we cocultured CD8^(+)T cells and Huh-7 cells to explore the regulatory effect of hepatoma cells on CD8^(+)T cells.Flow cytometry results revealed increased PD-1 expression and decreased secretion of perforin(PRF1)and granzyme B(GZMB)by CD8^(+)T cells in the co-culture group.Meanwhile,JC-1 staining was decreased and the levels of reactive oxygen species and apoptosis were increased in CD8^(+)T cells of the co-culture group;additionally,the mitochondria of these cells were swollen.When CD8^(+)T cells were treated with the mitochondrial protective and damaging agents,their function was restored and inhibited,respectively,through the mitochondrial damage and apoptotic pathways.Subsequently,complete medium without glutamine was used to culture cells.As expected,CD8^(+)T cells showed functional downregulation,mitochondrial damage,and apoptosis.CONCLUSION Glutamine deprivation impairs the function of infiltrating CD8^(+)T cells in hepatocellular carcinoma through the mitochondrial damage and apoptotic pathways.展开更多
Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and mortality.Mitochondria are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the oc...Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and mortality.Mitochondria are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the occurrence of CVD.The epigenetic mechanism of PM_(2.5)-triggered mitochondrial injury of cardiomyocytes is unclear.This study focused on the mi R-421/SIRT3 signaling pathway to investigate the regulatory mechanism in cardiac mitochondrial dynamics imbalance in rat H9c2 cells induced by PM_(2.5).Results illustrated that PM_(2.5)impaired mitochondrial function and caused dynamics homeostasis imbalance.Besides,PM_(2.5)up-regulated mi R-421 and down-regulated SIRT3 gene expression,along with decreasing p-FOXO3a(SIRT3 downstream target gene)and p-Parkin expression and triggering abnormal expression of fusion gene OPA1 and fission gene Drp1.Further,mi R-421 inhibitor(mi R-421i)and resveratrol significantly elevated the SIRT3 levels in H9c2 cells after PM_(2.5)exposure and mediated the expression of SOD2,OPA1 and Drp1,restoring the mitochondrial morphology and function.It suggests that mi R-421/SIRT3 pathway plays an epigenetic regulatory role in mitochondrial damage induced by PM_(2.5)and that mi R-421i and resveratrol exert protective effects against PM_(2.5)-incurred cardiotoxicity.展开更多
Mitochondrial damage is closely related to the occurrence of many diseases.However,accurate monitoring and reporting of mitochondrial damage are not easy.Here,we developed a small molecule fluorescent probe named CB-C...Mitochondrial damage is closely related to the occurrence of many diseases.However,accurate monitoring and reporting of mitochondrial damage are not easy.Here,we developed a small molecule fluorescent probe named CB-Cl,which has splendid spectral properties(large Stokes shift,strong affinity for RNA,etc.)and excellent targeting ability to intracellular mitochondria.After mitochondria were damaged by external stimuli,CB-Cl would light up the nucleolus as a signal reporter.The cascade imaging of mitochondria and nucleolus using CB-Cl can monitor and visualize the mitochondrial status in living cells in real-time.Based on the above advantages,the probe CB-Cl has reference significance for the related research of mitochondrial damage and the prevention and treatment of related diseases.展开更多
Tebuconazole exposure has been described as an increasing hazard to human health.An increasing number of recent studies have shown a positive association between tebuconazole exposure and cardiovascular disease risk,w...Tebuconazole exposure has been described as an increasing hazard to human health.An increasing number of recent studies have shown a positive association between tebuconazole exposure and cardiovascular disease risk,which is characterized by the reduction of adenosine triphosphate(ATP)synthesis.However,researches on the damage of tebuconazole exposure to energy metabolism and the related molecular mechanisms are limited.In the present study,male C57BL/6 mice were treated with tebuconazole at different low concentrations for 4 weeks.The results indicated that tebuconazole could accumulate in the heart and further induce the decrease of ATP content in the mouse heart.Importantly,tebuconazole induced an obvious shift in substrate utilization of fatty acid and glucose by disrupting their corresponding transporters(GLUT1,GLUT4,CD36,FABP3 and FATP1)expression,and significantly repressed the expression of mitochondrial biogenesis(Gabpa and Tfam)and oxidative phosphorylation(CS,Ndufa4,Sdhb,Cox5a and Atp5b)related genes in a dosedependent manner.Further investigation revealed that these alterations were related to the IRS1/AKT and PPARγ/RXRαpathways.These findings contribute to a better understanding of triazole fungicide-induced cardiovascular disease by revealing the key indicators associated with this phenomenon.展开更多
Objective:Studies have demonstrated that administering statins promptly following myocardial ischemia/reperfusion(MI/R)can confer cardioprotective benefits.This study investigates whether Lovastatin can modulate the Y...Objective:Studies have demonstrated that administering statins promptly following myocardial ischemia/reperfusion(MI/R)can confer cardioprotective benefits.This study investigates whether Lovastatin can modulate the Yes-associated protein/Transcriptional co-activator with PDZ-binding motif(YAP/TAZ)signaling pathway to mitigate cardiomyocyte injury caused by hypoxia/reoxygenation(H/R).Methods:The in vitro MI/R model was established by H/R in rat myocardial H9c2 cells,and the cells were pretreated with varying doses of Lovastatin before reoxygenation.The extent of cellular injury was evaluated by measuring the myocardial enzyme content and cell viability.The levels of oxidative stress and inflammatory factors were quantified by enzyme-linked immunosorbent assay(ELISA).Mitochondrial function was evaluated by detecting mitochondrial reactive oxide species(ROS),oxygen consumption rate(OCR),mitochondrial permeability transition pore(MPTP),adenosine 5′-triphosphate(ATP),mitochondrial membrane potential(MMP),and Ca^(2+).Western blotting(WB)and immunofluorescence assays were applied to detect the proteins related to apoptosis,autophagy,and YAP/TAZ signaling.YAP overexpression plasmid(Ov-YAP)was constructed for mechanism verification.Results:H/R leads to a reduction in H9c2 cell viability,and an elevation in the contents of myocardial enzymes,inflammatory factors,and oxidative stress.The apoptosis and autophagy were increased,and yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)expression levels were up-regulated in the H/R group.Nevertheless,all these changes were dose-dependently reversed by Lovastatin.Meanwhile,Lovastatin restored the levels of MMP,ATP,MPTP opening,and Ca^(2+),and reduced OCR in H9c2 cells exposed to H/R.Nevertheless,Ov-YAP markedly attenuated the function of Lovastatin on apoptosis,autophagy,inflammation,and oxidative stress in H9c2 cells exposed to H/R.Conclusion:The result indicated that Lovastatin played a protective role in H/R-induced H9c2 cells by inhibiting YAP/TAZ signaling.展开更多
Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 1...Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 181 clone 25(CHIKV 181/25)and the role of migrasomes in mitigating this damage.Using cultured cell lines,we assessed the impact of CHIKV infection on mitochondrial integrity and function,with particular emphasis on the viroporin proteins transframe(TF)and 6K.We utilized fluorescence microscopy and transmission electron microscopy to visualize the interplay between migrasome formation and damaged mitochondria.Additionally,calcium imaging assays were conducted to evaluate intracellular calcium levels,and RNA sequencing was performed to examine gene expression.Our results demonstrated that CHIKV infection leads to mitochondrial damage,mediated by the action of TF and 6K.Notably,migrasomes induced by nonstructural protein 1(nsP1)effectively clearing impaired mitochondria through mitocytosis.Furthermore,we identified the arginine residue R37 within the viroporin proteins of CHIKV as crucial for inducing mitochondrial damage through elevated intracellular calcium levels.Importantly,R37 within TF from other alphaviruses is also critical for mitochondrial damage.In conclusion,our findings elucidate the complex interplay between CHIKV and mitochondrial dysfunction,positioning migrasomes as potential mediators in alleviating CHIKVinduced mitochondrial damage.展开更多
Photothermal therapy (PTT) circumvents theconstraints of conventional treatments and has manifestedsubstantial potential for clinical applications. Nevertheless,the up-regulation of heat shock proteins (HSP) and mitoc...Photothermal therapy (PTT) circumvents theconstraints of conventional treatments and has manifestedsubstantial potential for clinical applications. Nevertheless,the up-regulation of heat shock proteins (HSP) and mitochondria-encoded genes within tumor cells endows themwith a high level of heat resistance, thereby limiting the ultimateefficacy of PTT. Herein, PtRhMo/Rh multi-metal-basednanozymes were designed by a one-step method for PTT andcascade enzymatic therapy. The PtRhMo/Rh nanozymes arecapable of combining multiple enzymatic activities (catalase,oxidase, glutathione peroxidase, NADH oxidase and peroxidase)for reactive oxygen radical boosting. With the help ofthe near-infrared laser, PtRhMo/Rh nanozymes can not onlykill tumor cells directly, but also down-regulate HSP70 leveland destroy the mitochondrial to weaken the heat-resistantability of tumor cells, further enhancing the effect of PTT.Overall, our work highlights a synergistic strategy for enzymatictherapy and enhanced PTT.展开更多
Alzheimer's disease(AD)is one of the most common neurodegenerative diseases among the elderly and it accounts for nearly 80%of all dementias.The pathogenesis of AD is complicated and enigmatic thus far.The mitocho...Alzheimer's disease(AD)is one of the most common neurodegenerative diseases among the elderly and it accounts for nearly 80%of all dementias.The pathogenesis of AD is complicated and enigmatic thus far.The mitochondrial cascade hypothesis assumes that mitochondrial damage may mediate,drive,or contribute to a variety of AD pathologies and may be the main factor in late-onset AD.Currently,there are no widely recognized drugs able to attenuate mitochondrial damage in AD.Notably,increasing evidence supports the efficacy of acupuncture for improving the mitochondrial structure and protecting mitochondrial functions in AD.This review reports the mechanisms by which acupuncture regulates mitochondrial dynamics,energy metabolism,calcium homeostasis and apoptosis.In conclusion,these findings suggest that AD mitochondrial dysfunction represents a reasonable therapeutic target and acupuncture could play a significant role in preventing and treating AD.展开更多
Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis(OA).However,the underlying mechanisms governing mitochondrial self...Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis(OA).However,the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive.In this study,we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes.Genetically overexpressing PTEN-induced putative kinase 1(PINK1)protects against cartilage degeneration by removing defective mitochondria.PINK1 knockout aggravated cartilage damage due to impaired mitophagy.SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism.Specifically,PINK1 phosphorylated PKM2 at the Ser127 site,preserving its active tetrameric form.This inhibited nuclear translocation and the interaction withβ-catenin,resulting in a metabolic shift and increased energy production.Finally,a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions.Overall,this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.展开更多
Hypertension represents a significant chronic non-infectious disease in China,where Qingda Granule(QDG)has traditionally been employed for its management.However,the mechanisms underlying QDG's kidney protective e...Hypertension represents a significant chronic non-infectious disease in China,where Qingda Granule(QDG)has traditionally been employed for its management.However,the mechanisms underlying QDG's kidney protective effects remain incompletely understood.This study investigates QDG's role in ameliorating hypertensive kidney injury(KI)and elucidates the associated mechanisms.Network analysis identified potential therapeutic targets related to mitochondrial function and the extracellular signal-regulated kinase(ERK)cascade.Ribonucleic acid(RNA)sequencing revealed differentially expressed genes(DEGs)in hypertensive mouse kidneys,which were enriched in mitochondrial-related functions and normalized by QDG treatment.QDG attenuated angiotensin II(Ang II)-induced blood pressure elevation and enhanced renal artery flow.Both cellular and animal experiments demonstrated that QDG inhibits the ERK/ribosomal S6 kinase 1(RSK1)signaling axis,thereby preventing Ang II-induced mitochondrial damage and renal cell apoptosis.ERK pathway inhibitors confirmed QDG's mechanism of action through the ERK/RSK1 pathway.These findings indicate that QDG ameliorates hypertensive KI by preserving mitochondrial function through modulation of the ERK/RSK1 network,presenting a novel therapeutic approach for managing hypertensive KI in clinical practice.展开更多
Clinical advances in the treatment of intracranial hemorrhage(ICH)are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury.Acrolein is a highly active unsaturat...Clinical advances in the treatment of intracranial hemorrhage(ICH)are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury.Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases.Our results indicated a significant increase in the level of acrolein after ICH in mouse brain.In primary neurons,acrolein induced an increase in mitochondrial fragmentation,loss of mitochondrial membrane potential,generation of reactive oxidative species,and release of mitochondrial cytochrome c.Mechanistically,acrolein facilitated the translocation of dynaminrelated protein 1(Drpl)from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission.Further studies found that treatment with hydralazine(an acrolein scavenger)significantly reversed Drpl translocation and the morphological damage of mitochondria after ICH.In parallel,the neural apoptosis,brain edema,and neurological functional deficits induced by ICH were also remarkably alleviated.In conclusion,our results identify acrolein as an important contributor to the secondary brain injury following ICH.Meanwhile,we uncovered a novel mechanism by which Drpl-mediated mitochondrial oxidative damage is involved in acroleininduced brain injury.展开更多
BACKGROUND: Some scholars believed that the neuronal injury after status epilepticus is apoptosis, the main evidence is the changes of expressions of various apoptosis related genes, such as immediate-early gene, p53 ...BACKGROUND: Some scholars believed that the neuronal injury after status epilepticus is apoptosis, the main evidence is the changes of expressions of various apoptosis related genes, such as immediate-early gene, p53 gene and genes of bcl-2 family, etc. But there is still no ultrastructural evidence for apoptosis. OBJECTIVE: To observe the ultrastructural damages of mitochondrion and nucleus and the changes of caspase expression in neurons of hippocampal CA3 region in rats with status epilepticus induced by kainic acid. DESIGN: A randomized controlled study. SETTING: Department of Anesthesiology and Department of Neurology, Qilu Hospital of Shandong University. MATERIALS: Seventy-five adult male Wistar rats of 250-300 g, clean degree, were provided by the experimental animal center of Shandong University. Kainic acid was purchased from Sigma Company (USA); rabbit anti-rat polyclonal antibody caspase-3 from Santa Cruz Company (USA). METHODS: The experiments were carried out in the Department of Anesthesiology, Qilu Hospital of Shandong University from October 2005 to February 2006. ① The 75 rats were randomly divided into experimental group (n =45) and control group (n =30). ② Model establishment, convulsion grading and the judging standards for status epilepticus: Rats in the experimental group were given intraperitoneal injection of kainic acid (10 mg/kg), and those in the control group were injected with saline of the same volume. The time of seizure was recorded and their behavioral manifestations were observed, and the seizure was terminated by intraperitoneal injection of diazepam (10 mg/kg). ③ Observation under electron microscope: At 3, 12 and 24 hours after status epilepticus respectively, bilateral hippocampal tissues were taken out, semithin sections of about 75 nm were prepared after fixation, dehydration and embedding, and then observed under H-800 transmission electron microscope. ④ Immunohistochemical detection: Bilateral hippocampi were removed at 3, 12 and 24 hours after status epilepticus respectively, the fixation, dehydration, transparence, wax immersion and embedding were performed, then serial sections of CA3 region were immunohistochemically determined by the SABC method. Leica QWinV3 image analytical software was applied, then the average number and average gray value of positive cells were calculated. MAIN OUTCOME MEASURES: Results of observation under electron microscope, that of immunohistochemical staining of neurons in hippocampal CA3 region; Comparison of number of caspase-3 positive cells and gray value. RESULTS: All the 75 Wistar rats were involved in the analysis of results. ① Results of observation under electron microscope: At 3 hours after status epilepticus, swelling crista and membranous disintegration were observed under electron microscope. At 24 hours, obvious nuclear changes occurred, and manifested as the side-aggegation of chromatins. ② Results of immunohistochemical detection: In the experimental group, the number of caspase-3 positive cells at 3 hours after status epilepticus had no obvious difference as compared with that in the control group (P > 0.05); At 12 hours, the number and gray value of caspase-3 positive cells in the experimental group were higher than those in the control group (10.49±0.68 vs. 5.33±0.43; 45.57±2.27 vs. 19.79±0.33, P < 0.05), the same results were also observed at 24 hours (37.36±0.57 vs. 5.12±0.47; 115.24±1.22 vs. 18.73±0.42, P < 0.01). CONCLUSION: In the rat models of status epilepticus induced by kainic acid, mitochondrial damage was earlier than the increase of caspase-3 expression and nuclear changes, which suggested that mitochondrion was the key link for the neuronal death after status epilepticus.展开更多
Cervical cancer stands is a formidablemalignancy that poses a significant threat towomen’s health.Calcium overload,a minimally invasive tumor treatment,aims to accumulate an excessive concentration of Ca^(2+)within m...Cervical cancer stands is a formidablemalignancy that poses a significant threat towomen’s health.Calcium overload,a minimally invasive tumor treatment,aims to accumulate an excessive concentration of Ca^(2+)within mitochondria,triggering apoptosis.Copper sulfide(CuS)represents a photothermal mediator for tumor hyperthermia.However,relying solely on thermotherapy often proves insufficient in controlling tumor growth.Curcumin(CUR),an herbal compound with anti-cancer properties,inhibits the efflux of exogenous Ca^(2+)while promoting its excretion from the endoplasmic reticulum into the cytoplasm.To harness these therapeutic modalities,we have developed a nanoplatform that incorporates hollow CuS nanoparticles(NPs)adorned with multiple CaCO_(3) particles and internally loaded with CUR.This nanocomposite exhibits high uptake and easy escape from lysosomes,along with the degradation of surrounding CaCO3,provoking the generation of abundant exogenous Ca^(2+)in situ,ultimately damaging the mitochondria of diseased cells.Impressively,under laser excitation,the CuS NPs demonstrate a photothermal effect that accelerates the degradation of CaCO_(3),synergistically enhancing the antitumor effect through photothermal therapy.Additionally,fluorescence imaging reveals the distribution of these nanovehicles in vivo,indicating their effective accumulation at the tumor site.This nanoplatform shows promising outcomes for tumor-targeting and the effective treatment in a murine model of cervical cancer,achieved through cascade enhancement of calcium overload-based dual therapy.展开更多
Mitochondria are crucial sites for protein quality control within cells.When mitochondrial stress is triggered by protein misfolding,it can accelerate abnormal protein aggregation,potentially inducing various diseases...Mitochondria are crucial sites for protein quality control within cells.When mitochondrial stress is triggered by protein misfolding,it can accelerate abnormal protein aggregation,potentially inducing various diseases.This study developed a cascade-responsive sensor,named AggHX,to monitor the microenvironment of protein aggregation induced by zinc(II)ions and the accompanying mitochondrial dysfunction.The AggHX consists of two key components:(1)A Zn^(2+) þrecognition group for triggering a fluorescent enhance response,and(2)a near-infrared BODIPY scaffold that detects viscosity changes in cell aggregation via HaloTag.This sensor's mechanism of action is elucidated through photochemical and biochemical characterizations.To further investigate the relationship between protein aggregation and mitochondrial homeostasis,we employ fluorescence lifetime imaging microscopy to assess viscosity changes in protein aggregates under intracellular Zn2þstress.This research provides insights into the dynamic behavior and spatial distribution of protein aggregates and mitochondria,contributing to a deeper understanding of their physiological roles in cellular processes and potential implications in disease pathology.展开更多
Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acu...Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acute spinal cord injury. Results showed that mitochondria had an irregular shape, and increased in size. Mitochondrial cristae were disordered and mitochondrial membrane rupture was visible at 2–24 hours after injury. Fusion protein mitofusin 1 expression gradually increased, peaked at 8 hours after injury, and then decreased to its lowest level at 24 hours. Expression of dynamin-related protein 1, amitochondrial fission protein, showed the opposite kinetics. At 2–24 hours after acute spinal cord injury, malondialdehyde content, cytochrome c levels and caspase-3 expression were increased, but glutathione content, adenosine triphosphate content, Na＋-K＋-ATPase activity and mitochondrial membrane potential were gradually reduced. Furthermore, mitochondrial morphology altered during the acute stage of spinal cord injury. Fusion was important within the first 8 hours, but fission played a key role at 24 hours. Oxidative stress was inhibited, biological productivity was diminished, and mitochondrial membrane potential and permeability were reduced in the acute stage of injury. In summary, mitochondrial apoptosis is activated when the time of spinal cord injury is prolonged.展开更多
Schizophrenia(SCZ)is a severe mental disorder with significant impacts on individuals,families,and society.Previous research has indicated that SCZ patients will commonly face substantial impairments in mitochondrial ...Schizophrenia(SCZ)is a severe mental disorder with significant impacts on individuals,families,and society.Previous research has indicated that SCZ patients will commonly face substantial impairments in mitochondrial function and oxidative phosphorylation in the brain.Cell-free DNA(cf-DNA),serving as a direct biomarker of apoptosis,offers a valuable vantage point to understand the complex cellular mechanisms underlying SCZ.This review is to explore the role of cf-DNA in the etiology and progression of SCZ and evaluate the potential of cf-DNA within extracellular vesicles(EVs)as a diagnostic biomarker.A review approach was employed to gather and analyze relevant literature on the role of cf-DNA in SCZ,especially focusing on the potential of cf-DNA within EVs as a diagnostic biomarker.This review found that cf-DNA within EVs holds the potential to improve diagnostic methods.It can offer more accurate and sensitive means for detecting SCZ.Moreover,it has the ability to optimize disease management strategies by providing information about the disease state.Also,it can promote the development of pharmacological treatments for SCZ.Integrating cf-DNA analysis into clinical practice can help clinicians utilize cf-DNA levels and its unique characteristics for early and accurate diagnosis.The analysis of cf-DNA,particularly cf-DNA within EVs,has significant potential in the context of SCZ.It can transform our understanding of the disorder,improve diagnostic approaches,optimize disease management,and foster the development of pharmacological treatments.展开更多
Bisphenol A is a common environmental factor and endocrine disruptor that exerts a negative impact on male reproductive ability.By exploring bisphenol A-induced testicular cell death using the Institute of Cancer Rese...Bisphenol A is a common environmental factor and endocrine disruptor that exerts a negative impact on male reproductive ability.By exploring bisphenol A-induced testicular cell death using the Institute of Cancer Research(ICR)mouse model,we found that a ferroptosis phenomenon may exist.Mice were divided into six groups and administered different doses of bisphenol A via intragastric gavage once daily for 45 consecutive days.Serum was then collected to determine the levels of superoxide dismutase and malondialdehyde.Epididymal sperm was also collected for semen analysis,and testicular tissue was collected for ferritin content determination,electron microscope observation of mitochondrial morphology,immunohistochemistry,real-time quantitative polymerase chain reaction,and western blot analysis.Exposure to bisphenol A was found to decrease sperm quality and cause oxidative damage,iron accumulation,and mitochondrial damage in the testes of mice.In addition,bisphenol A was confirmed to affect the expression of the ferroptosis-related genes,glutathione peroxidase 4(GPX4),ferritin heavy chain 1(FTH1),cyclooxygenase 2(COX2),and acyl-CoA synthetase 4(ACSL4)in mouse testicular tissues.Accordingly,we speculate that bisphenol A induces oxidative stress,which leads to the ferroptosis of testicular cells.Overall,the inhibition of ferroptosis may be a potential strategy to reduce male reproductive toxicity caused by bisphenol A.展开更多
Autophagy plays an important role in the interaction between viruses and host cells.SARS-CoV-2 infection can disrupt the autophagy process in target cells.However,the precise molecular mechanism is still unknown.In th...Autophagy plays an important role in the interaction between viruses and host cells.SARS-CoV-2 infection can disrupt the autophagy process in target cells.However,the precise molecular mechanism is still unknown.In this study,we discovered that the Nsp8 of SARS-CoV-2 could cause an increasing accumulation of autophagosomes by preventing the fusion of autophagosomes and lysosomes.From further investigation,we found that Nsp8 was present on mitochondria and can damage mitochondria to initiate mitophagy.The results of experiments with immunofluorescence revealed that Nsp8 induced incomplete mitophagy.Moreover,both domains of Nsp8 orchestrated their function during Nsp8-induced mitophagy,in which the N-terminal domain colocalized with mitochondria and the C-terminal domain induced auto/mitophagy.This novel finding expands our understanding of the function of Nsp8 in promoting mitochondrial damage and inducing incomplete mitophagy,which helps us to understand the etiology of COVID-19 as well as open up new pathways for creating SARS-CoV-2 treatment methods.展开更多
基金supported by the National Natural Science Foundation of China,No.81274005Medical Science Research,Health Department of Hebei Province,No.20110173,20090588Hebei Education Department Science Foundation,No.2007302
文摘Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2＋ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative diseases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.
基金supported by NIH NS069726 and NS094539America Heart Association 13GRANT17020004(to SD)
文摘Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,
基金Supported by High-End Talent Funding Project in Hebei Province,No.A202003005Hebei Provincial Health Commission Office,No.G2019074Natural Science Foundation of Hebei Province,No.H2019209355。
文摘BACKGROUND The functions of infiltrating CD8^(+)T cells are often impaired due to tumor cells causing nutrient deprivation in the tumor microenvironment.Thus,the mechanisms of CD8^(+)T cell dysfunction have become a hot research topic,and there is increased interest on how changes in metabolomics correlate with CD8^(+)T cell dysfunction.AIM To investigate whether and how glutamine metabolism affects the function of infiltrating CD8^(+)T cells in hepatocellular carcinoma.METHODS Immunohistochemical staining and immunofluorescence were performed on surgically resected liver tissues from patients.Differentially expressed genes in infiltrating CD8^(+)T cells in hepatocellular carcinoma were detected using RNA sequencing.Activated CD8^(+)T cells were co-cultured with Huh-7 cells for 3 d.The function and mitochondrial status of CD8^(+)T cells were analyzed by flow cytometry,quantitative real-time polymerase chain reaction,and transmission electron microscopy.Next,CD8^(+)T cells were treated with the mitochondrial protective and damaging agents.Functional alterations in CD8^(+)T cells were detected by flow cytometry.Then,complete medium without glutamine was used to culture cells and their functional changes and mitochondrial status were detected.RESULTS There were a large number of infiltrating PD-1+CD8^(+)T cells in liver cancer tissues.Next,we cocultured CD8^(+)T cells and Huh-7 cells to explore the regulatory effect of hepatoma cells on CD8^(+)T cells.Flow cytometry results revealed increased PD-1 expression and decreased secretion of perforin(PRF1)and granzyme B(GZMB)by CD8^(+)T cells in the co-culture group.Meanwhile,JC-1 staining was decreased and the levels of reactive oxygen species and apoptosis were increased in CD8^(+)T cells of the co-culture group;additionally,the mitochondria of these cells were swollen.When CD8^(+)T cells were treated with the mitochondrial protective and damaging agents,their function was restored and inhibited,respectively,through the mitochondrial damage and apoptotic pathways.Subsequently,complete medium without glutamine was used to culture cells.As expected,CD8^(+)T cells showed functional downregulation,mitochondrial damage,and apoptosis.CONCLUSION Glutamine deprivation impairs the function of infiltrating CD8^(+)T cells in hepatocellular carcinoma through the mitochondrial damage and apoptotic pathways.
基金supported by the National Natural Science Foundation of China(No.22176116)the Natural Science Foundation of Shanxi Province in China(No.201801D121260)the Hundred Talents Program of Shanxi Province in China(2017-7)。
文摘Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and mortality.Mitochondria are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the occurrence of CVD.The epigenetic mechanism of PM_(2.5)-triggered mitochondrial injury of cardiomyocytes is unclear.This study focused on the mi R-421/SIRT3 signaling pathway to investigate the regulatory mechanism in cardiac mitochondrial dynamics imbalance in rat H9c2 cells induced by PM_(2.5).Results illustrated that PM_(2.5)impaired mitochondrial function and caused dynamics homeostasis imbalance.Besides,PM_(2.5)up-regulated mi R-421 and down-regulated SIRT3 gene expression,along with decreasing p-FOXO3a(SIRT3 downstream target gene)and p-Parkin expression and triggering abnormal expression of fusion gene OPA1 and fission gene Drp1.Further,mi R-421 inhibitor(mi R-421i)and resveratrol significantly elevated the SIRT3 levels in H9c2 cells after PM_(2.5)exposure and mediated the expression of SOD2,OPA1 and Drp1,restoring the mitochondrial morphology and function.It suggests that mi R-421/SIRT3 pathway plays an epigenetic regulatory role in mitochondrial damage induced by PM_(2.5)and that mi R-421i and resveratrol exert protective effects against PM_(2.5)-incurred cardiotoxicity.
基金the Shenzhen Science and Technology Research and Development Funds(No.JCYJ20190806155409104)National Natural Science Foundation of China(Nos.52150222,21672130 and 52073163)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2019A1515110356)the Qilu Young Scholars Program of Shandong University.
文摘Mitochondrial damage is closely related to the occurrence of many diseases.However,accurate monitoring and reporting of mitochondrial damage are not easy.Here,we developed a small molecule fluorescent probe named CB-Cl,which has splendid spectral properties(large Stokes shift,strong affinity for RNA,etc.)and excellent targeting ability to intracellular mitochondria.After mitochondria were damaged by external stimuli,CB-Cl would light up the nucleolus as a signal reporter.The cascade imaging of mitochondria and nucleolus using CB-Cl can monitor and visualize the mitochondrial status in living cells in real-time.Based on the above advantages,the probe CB-Cl has reference significance for the related research of mitochondrial damage and the prevention and treatment of related diseases.
基金supported by the National Science Foundation of China (Nos.21806094,22036005,22176119,22076108 and 21906098)the Natural Science Foundation of Shanxi Province (No.201901D211123)。
文摘Tebuconazole exposure has been described as an increasing hazard to human health.An increasing number of recent studies have shown a positive association between tebuconazole exposure and cardiovascular disease risk,which is characterized by the reduction of adenosine triphosphate(ATP)synthesis.However,researches on the damage of tebuconazole exposure to energy metabolism and the related molecular mechanisms are limited.In the present study,male C57BL/6 mice were treated with tebuconazole at different low concentrations for 4 weeks.The results indicated that tebuconazole could accumulate in the heart and further induce the decrease of ATP content in the mouse heart.Importantly,tebuconazole induced an obvious shift in substrate utilization of fatty acid and glucose by disrupting their corresponding transporters(GLUT1,GLUT4,CD36,FABP3 and FATP1)expression,and significantly repressed the expression of mitochondrial biogenesis(Gabpa and Tfam)and oxidative phosphorylation(CS,Ndufa4,Sdhb,Cox5a and Atp5b)related genes in a dosedependent manner.Further investigation revealed that these alterations were related to the IRS1/AKT and PPARγ/RXRαpathways.These findings contribute to a better understanding of triazole fungicide-induced cardiovascular disease by revealing the key indicators associated with this phenomenon.
文摘Objective:Studies have demonstrated that administering statins promptly following myocardial ischemia/reperfusion(MI/R)can confer cardioprotective benefits.This study investigates whether Lovastatin can modulate the Yes-associated protein/Transcriptional co-activator with PDZ-binding motif(YAP/TAZ)signaling pathway to mitigate cardiomyocyte injury caused by hypoxia/reoxygenation(H/R).Methods:The in vitro MI/R model was established by H/R in rat myocardial H9c2 cells,and the cells were pretreated with varying doses of Lovastatin before reoxygenation.The extent of cellular injury was evaluated by measuring the myocardial enzyme content and cell viability.The levels of oxidative stress and inflammatory factors were quantified by enzyme-linked immunosorbent assay(ELISA).Mitochondrial function was evaluated by detecting mitochondrial reactive oxide species(ROS),oxygen consumption rate(OCR),mitochondrial permeability transition pore(MPTP),adenosine 5′-triphosphate(ATP),mitochondrial membrane potential(MMP),and Ca^(2+).Western blotting(WB)and immunofluorescence assays were applied to detect the proteins related to apoptosis,autophagy,and YAP/TAZ signaling.YAP overexpression plasmid(Ov-YAP)was constructed for mechanism verification.Results:H/R leads to a reduction in H9c2 cell viability,and an elevation in the contents of myocardial enzymes,inflammatory factors,and oxidative stress.The apoptosis and autophagy were increased,and yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)expression levels were up-regulated in the H/R group.Nevertheless,all these changes were dose-dependently reversed by Lovastatin.Meanwhile,Lovastatin restored the levels of MMP,ATP,MPTP opening,and Ca^(2+),and reduced OCR in H9c2 cells exposed to H/R.Nevertheless,Ov-YAP markedly attenuated the function of Lovastatin on apoptosis,autophagy,inflammation,and oxidative stress in H9c2 cells exposed to H/R.Conclusion:The result indicated that Lovastatin played a protective role in H/R-induced H9c2 cells by inhibiting YAP/TAZ signaling.
基金supported by grants from Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project(grant number 2025ZD01903602 to L.Z.)Shandong Provincial Natural Science Foundation(grant number ZR2024MH017 to L.Z.)+2 种基金National Natural Science Foundation of China(grant numbers 82272306 and 82072270 to L.Z.)Taishan Scholars Program(grant number tstp20221142 to L.Z.)Joint Innovation Team for Clinical&Basic Research(grant number 202409 to L.Z.)。
文摘Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 181 clone 25(CHIKV 181/25)and the role of migrasomes in mitigating this damage.Using cultured cell lines,we assessed the impact of CHIKV infection on mitochondrial integrity and function,with particular emphasis on the viroporin proteins transframe(TF)and 6K.We utilized fluorescence microscopy and transmission electron microscopy to visualize the interplay between migrasome formation and damaged mitochondria.Additionally,calcium imaging assays were conducted to evaluate intracellular calcium levels,and RNA sequencing was performed to examine gene expression.Our results demonstrated that CHIKV infection leads to mitochondrial damage,mediated by the action of TF and 6K.Notably,migrasomes induced by nonstructural protein 1(nsP1)effectively clearing impaired mitochondria through mitocytosis.Furthermore,we identified the arginine residue R37 within the viroporin proteins of CHIKV as crucial for inducing mitochondrial damage through elevated intracellular calcium levels.Importantly,R37 within TF from other alphaviruses is also critical for mitochondrial damage.In conclusion,our findings elucidate the complex interplay between CHIKV and mitochondrial dysfunction,positioning migrasomes as potential mediators in alleviating CHIKVinduced mitochondrial damage.
基金financially supported by the Shenzhen Medical Research Fund (B2402032)the National Key Research and Development Program of China (2023YFB4705900)+3 种基金the Natural Science Foundation of Top Talent of Shenzhen Technology University (GDRC202303)the National Natural Science Foundation of China (62373259)the Common University Innovation Team Project of Guangdong (2021KCXTD041)the Foundation of Education Department of Guangdong Province, China (2022ZDJS115)。
文摘Photothermal therapy (PTT) circumvents theconstraints of conventional treatments and has manifestedsubstantial potential for clinical applications. Nevertheless,the up-regulation of heat shock proteins (HSP) and mitochondria-encoded genes within tumor cells endows themwith a high level of heat resistance, thereby limiting the ultimateefficacy of PTT. Herein, PtRhMo/Rh multi-metal-basednanozymes were designed by a one-step method for PTT andcascade enzymatic therapy. The PtRhMo/Rh nanozymes arecapable of combining multiple enzymatic activities (catalase,oxidase, glutathione peroxidase, NADH oxidase and peroxidase)for reactive oxygen radical boosting. With the help ofthe near-infrared laser, PtRhMo/Rh nanozymes can not onlykill tumor cells directly, but also down-regulate HSP70 leveland destroy the mitochondrial to weaken the heat-resistantability of tumor cells, further enhancing the effect of PTT.Overall, our work highlights a synergistic strategy for enzymatictherapy and enhanced PTT.
基金Supported by Science and Technology Innovation Projects(No.CI2021A03519)"The Belt and Road Initiative"International Cooperation Project Funded by China Academy of Chinese Medical Sciences。
文摘Alzheimer's disease(AD)is one of the most common neurodegenerative diseases among the elderly and it accounts for nearly 80%of all dementias.The pathogenesis of AD is complicated and enigmatic thus far.The mitochondrial cascade hypothesis assumes that mitochondrial damage may mediate,drive,or contribute to a variety of AD pathologies and may be the main factor in late-onset AD.Currently,there are no widely recognized drugs able to attenuate mitochondrial damage in AD.Notably,increasing evidence supports the efficacy of acupuncture for improving the mitochondrial structure and protecting mitochondrial functions in AD.This review reports the mechanisms by which acupuncture regulates mitochondrial dynamics,energy metabolism,calcium homeostasis and apoptosis.In conclusion,these findings suggest that AD mitochondrial dysfunction represents a reasonable therapeutic target and acupuncture could play a significant role in preventing and treating AD.
基金supported by grants from National Nature Science Foundation of China(82272494,82472452,82402864)National Key R&D Program of China(2022YFC2502902)+4 种基金Key Project of Jiangsu Health Commission(K2023079)Natural Science Foundation of Jiangsu Province(BK20240368)Basic Research Pilot Project Suzhou(SSD2024062),China Postdoctoral Science Foundation(2024M762313)Boxi Youth Natural Science Foundation(BXQN2023014)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis(OA).However,the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive.In this study,we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes.Genetically overexpressing PTEN-induced putative kinase 1(PINK1)protects against cartilage degeneration by removing defective mitochondria.PINK1 knockout aggravated cartilage damage due to impaired mitophagy.SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism.Specifically,PINK1 phosphorylated PKM2 at the Ser127 site,preserving its active tetrameric form.This inhibited nuclear translocation and the interaction withβ-catenin,resulting in a metabolic shift and increased energy production.Finally,a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions.Overall,this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.
基金supported by the National Natural Science Foundation of China(Nos.U22A20372,82204662,82374359,82204662)the Fujian Province Natural Science Foundation(Nos.2022J01369,2021J1942)+1 种基金the Developmental Fund of Chen Keji Integrative Medicine(No.CKJ2022010)the Fujian Natural Science Foundation for Distinguished Young Scholars(No.2024J010032)。
文摘Hypertension represents a significant chronic non-infectious disease in China,where Qingda Granule(QDG)has traditionally been employed for its management.However,the mechanisms underlying QDG's kidney protective effects remain incompletely understood.This study investigates QDG's role in ameliorating hypertensive kidney injury(KI)and elucidates the associated mechanisms.Network analysis identified potential therapeutic targets related to mitochondrial function and the extracellular signal-regulated kinase(ERK)cascade.Ribonucleic acid(RNA)sequencing revealed differentially expressed genes(DEGs)in hypertensive mouse kidneys,which were enriched in mitochondrial-related functions and normalized by QDG treatment.QDG attenuated angiotensin II(Ang II)-induced blood pressure elevation and enhanced renal artery flow.Both cellular and animal experiments demonstrated that QDG inhibits the ERK/ribosomal S6 kinase 1(RSK1)signaling axis,thereby preventing Ang II-induced mitochondrial damage and renal cell apoptosis.ERK pathway inhibitors confirmed QDG's mechanism of action through the ERK/RSK1 pathway.These findings indicate that QDG ameliorates hypertensive KI by preserving mitochondrial function through modulation of the ERK/RSK1 network,presenting a novel therapeutic approach for managing hypertensive KI in clinical practice.
基金This work was supported by grants from the National Natural Science Foundation of China(81630027,81571215)and the Chang Jiang Scholar Program of China.
文摘Clinical advances in the treatment of intracranial hemorrhage(ICH)are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury.Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases.Our results indicated a significant increase in the level of acrolein after ICH in mouse brain.In primary neurons,acrolein induced an increase in mitochondrial fragmentation,loss of mitochondrial membrane potential,generation of reactive oxidative species,and release of mitochondrial cytochrome c.Mechanistically,acrolein facilitated the translocation of dynaminrelated protein 1(Drpl)from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission.Further studies found that treatment with hydralazine(an acrolein scavenger)significantly reversed Drpl translocation and the morphological damage of mitochondria after ICH.In parallel,the neural apoptosis,brain edema,and neurological functional deficits induced by ICH were also remarkably alleviated.In conclusion,our results identify acrolein as an important contributor to the secondary brain injury following ICH.Meanwhile,we uncovered a novel mechanism by which Drpl-mediated mitochondrial oxidative damage is involved in acroleininduced brain injury.
文摘BACKGROUND: Some scholars believed that the neuronal injury after status epilepticus is apoptosis, the main evidence is the changes of expressions of various apoptosis related genes, such as immediate-early gene, p53 gene and genes of bcl-2 family, etc. But there is still no ultrastructural evidence for apoptosis. OBJECTIVE: To observe the ultrastructural damages of mitochondrion and nucleus and the changes of caspase expression in neurons of hippocampal CA3 region in rats with status epilepticus induced by kainic acid. DESIGN: A randomized controlled study. SETTING: Department of Anesthesiology and Department of Neurology, Qilu Hospital of Shandong University. MATERIALS: Seventy-five adult male Wistar rats of 250-300 g, clean degree, were provided by the experimental animal center of Shandong University. Kainic acid was purchased from Sigma Company (USA); rabbit anti-rat polyclonal antibody caspase-3 from Santa Cruz Company (USA). METHODS: The experiments were carried out in the Department of Anesthesiology, Qilu Hospital of Shandong University from October 2005 to February 2006. ① The 75 rats were randomly divided into experimental group (n =45) and control group (n =30). ② Model establishment, convulsion grading and the judging standards for status epilepticus: Rats in the experimental group were given intraperitoneal injection of kainic acid (10 mg/kg), and those in the control group were injected with saline of the same volume. The time of seizure was recorded and their behavioral manifestations were observed, and the seizure was terminated by intraperitoneal injection of diazepam (10 mg/kg). ③ Observation under electron microscope: At 3, 12 and 24 hours after status epilepticus respectively, bilateral hippocampal tissues were taken out, semithin sections of about 75 nm were prepared after fixation, dehydration and embedding, and then observed under H-800 transmission electron microscope. ④ Immunohistochemical detection: Bilateral hippocampi were removed at 3, 12 and 24 hours after status epilepticus respectively, the fixation, dehydration, transparence, wax immersion and embedding were performed, then serial sections of CA3 region were immunohistochemically determined by the SABC method. Leica QWinV3 image analytical software was applied, then the average number and average gray value of positive cells were calculated. MAIN OUTCOME MEASURES: Results of observation under electron microscope, that of immunohistochemical staining of neurons in hippocampal CA3 region; Comparison of number of caspase-3 positive cells and gray value. RESULTS: All the 75 Wistar rats were involved in the analysis of results. ① Results of observation under electron microscope: At 3 hours after status epilepticus, swelling crista and membranous disintegration were observed under electron microscope. At 24 hours, obvious nuclear changes occurred, and manifested as the side-aggegation of chromatins. ② Results of immunohistochemical detection: In the experimental group, the number of caspase-3 positive cells at 3 hours after status epilepticus had no obvious difference as compared with that in the control group (P > 0.05); At 12 hours, the number and gray value of caspase-3 positive cells in the experimental group were higher than those in the control group (10.49±0.68 vs. 5.33±0.43; 45.57±2.27 vs. 19.79±0.33, P < 0.05), the same results were also observed at 24 hours (37.36±0.57 vs. 5.12±0.47; 115.24±1.22 vs. 18.73±0.42, P < 0.01). CONCLUSION: In the rat models of status epilepticus induced by kainic acid, mitochondrial damage was earlier than the increase of caspase-3 expression and nuclear changes, which suggested that mitochondrion was the key link for the neuronal death after status epilepticus.
基金This research was sponsored by the key research program of Ningbo(No.2023Z210)funded by Ningbo Natural Science Foundation(No.202003N4006)the Joint Research Funds of Department of Science&Technology of Shaanxi Province,Northwestern Polytechnical University(No.2020GXLH-Z-017).
文摘Cervical cancer stands is a formidablemalignancy that poses a significant threat towomen’s health.Calcium overload,a minimally invasive tumor treatment,aims to accumulate an excessive concentration of Ca^(2+)within mitochondria,triggering apoptosis.Copper sulfide(CuS)represents a photothermal mediator for tumor hyperthermia.However,relying solely on thermotherapy often proves insufficient in controlling tumor growth.Curcumin(CUR),an herbal compound with anti-cancer properties,inhibits the efflux of exogenous Ca^(2+)while promoting its excretion from the endoplasmic reticulum into the cytoplasm.To harness these therapeutic modalities,we have developed a nanoplatform that incorporates hollow CuS nanoparticles(NPs)adorned with multiple CaCO_(3) particles and internally loaded with CUR.This nanocomposite exhibits high uptake and easy escape from lysosomes,along with the degradation of surrounding CaCO3,provoking the generation of abundant exogenous Ca^(2+)in situ,ultimately damaging the mitochondria of diseased cells.Impressively,under laser excitation,the CuS NPs demonstrate a photothermal effect that accelerates the degradation of CaCO_(3),synergistically enhancing the antitumor effect through photothermal therapy.Additionally,fluorescence imaging reveals the distribution of these nanovehicles in vivo,indicating their effective accumulation at the tumor site.This nanoplatform shows promising outcomes for tumor-targeting and the effective treatment in a murine model of cervical cancer,achieved through cascade enhancement of calcium overload-based dual therapy.
基金support from the Qinglan Project of Jiangsu Province of China,National Natural Science Foundation of China(Grant No.22007048)the Natural Science Foundation of Jiangsu Basic Research Program(BK20221324).
文摘Mitochondria are crucial sites for protein quality control within cells.When mitochondrial stress is triggered by protein misfolding,it can accelerate abnormal protein aggregation,potentially inducing various diseases.This study developed a cascade-responsive sensor,named AggHX,to monitor the microenvironment of protein aggregation induced by zinc(II)ions and the accompanying mitochondrial dysfunction.The AggHX consists of two key components:(1)A Zn^(2+) þrecognition group for triggering a fluorescent enhance response,and(2)a near-infrared BODIPY scaffold that detects viscosity changes in cell aggregation via HaloTag.This sensor's mechanism of action is elucidated through photochemical and biochemical characterizations.To further investigate the relationship between protein aggregation and mitochondrial homeostasis,we employ fluorescence lifetime imaging microscopy to assess viscosity changes in protein aggregates under intracellular Zn2þstress.This research provides insights into the dynamic behavior and spatial distribution of protein aggregates and mitochondria,contributing to a deeper understanding of their physiological roles in cellular processes and potential implications in disease pathology.
基金supported by the National Natural Science Foundation of China,No.81272074the Scientific Research Foundation Project for Doctors in Liaoning Province of China,No.20121094+1 种基金Aohongboze Graduate Sci-tech Innovation Foundationthe President Fund of Liaoning Medical University of China,No.2013003
文摘Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acute spinal cord injury. Results showed that mitochondria had an irregular shape, and increased in size. Mitochondrial cristae were disordered and mitochondrial membrane rupture was visible at 2–24 hours after injury. Fusion protein mitofusin 1 expression gradually increased, peaked at 8 hours after injury, and then decreased to its lowest level at 24 hours. Expression of dynamin-related protein 1, amitochondrial fission protein, showed the opposite kinetics. At 2–24 hours after acute spinal cord injury, malondialdehyde content, cytochrome c levels and caspase-3 expression were increased, but glutathione content, adenosine triphosphate content, Na＋-K＋-ATPase activity and mitochondrial membrane potential were gradually reduced. Furthermore, mitochondrial morphology altered during the acute stage of spinal cord injury. Fusion was important within the first 8 hours, but fission played a key role at 24 hours. Oxidative stress was inhibited, biological productivity was diminished, and mitochondrial membrane potential and permeability were reduced in the acute stage of injury. In summary, mitochondrial apoptosis is activated when the time of spinal cord injury is prolonged.
基金Supported by Natural Science Foundation of Inner Mongolia Autonomous Region,No.2024LHMS08003Science and Technology Program of the Joint Fund of Scientific Research for the Public Hospitals of Inner Mongolia Academy of Medical Sciences,No.2024GLLH0844.
文摘Schizophrenia(SCZ)is a severe mental disorder with significant impacts on individuals,families,and society.Previous research has indicated that SCZ patients will commonly face substantial impairments in mitochondrial function and oxidative phosphorylation in the brain.Cell-free DNA(cf-DNA),serving as a direct biomarker of apoptosis,offers a valuable vantage point to understand the complex cellular mechanisms underlying SCZ.This review is to explore the role of cf-DNA in the etiology and progression of SCZ and evaluate the potential of cf-DNA within extracellular vesicles(EVs)as a diagnostic biomarker.A review approach was employed to gather and analyze relevant literature on the role of cf-DNA in SCZ,especially focusing on the potential of cf-DNA within EVs as a diagnostic biomarker.This review found that cf-DNA within EVs holds the potential to improve diagnostic methods.It can offer more accurate and sensitive means for detecting SCZ.Moreover,it has the ability to optimize disease management strategies by providing information about the disease state.Also,it can promote the development of pharmacological treatments for SCZ.Integrating cf-DNA analysis into clinical practice can help clinicians utilize cf-DNA levels and its unique characteristics for early and accurate diagnosis.The analysis of cf-DNA,particularly cf-DNA within EVs,has significant potential in the context of SCZ.It can transform our understanding of the disorder,improve diagnostic approaches,optimize disease management,and foster the development of pharmacological treatments.
基金This work was supported by grant from the National Natural Science Foundation of China(No.8207152171 and No.82205166)。
文摘Bisphenol A is a common environmental factor and endocrine disruptor that exerts a negative impact on male reproductive ability.By exploring bisphenol A-induced testicular cell death using the Institute of Cancer Research(ICR)mouse model,we found that a ferroptosis phenomenon may exist.Mice were divided into six groups and administered different doses of bisphenol A via intragastric gavage once daily for 45 consecutive days.Serum was then collected to determine the levels of superoxide dismutase and malondialdehyde.Epididymal sperm was also collected for semen analysis,and testicular tissue was collected for ferritin content determination,electron microscope observation of mitochondrial morphology,immunohistochemistry,real-time quantitative polymerase chain reaction,and western blot analysis.Exposure to bisphenol A was found to decrease sperm quality and cause oxidative damage,iron accumulation,and mitochondrial damage in the testes of mice.In addition,bisphenol A was confirmed to affect the expression of the ferroptosis-related genes,glutathione peroxidase 4(GPX4),ferritin heavy chain 1(FTH1),cyclooxygenase 2(COX2),and acyl-CoA synthetase 4(ACSL4)in mouse testicular tissues.Accordingly,we speculate that bisphenol A induces oxidative stress,which leads to the ferroptosis of testicular cells.Overall,the inhibition of ferroptosis may be a potential strategy to reduce male reproductive toxicity caused by bisphenol A.
基金supported by the National Natural Science Foundation of China (grant numbers 32100131 and 31670716)Wuhan Science and Technology Bureau[grant numbers 2020020601012318]+1 种基金Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine) (grant numbers WDCM2022008)Jianghan University (grant numbers 08190006,06210035,2021yb138 and 2019037).
文摘Autophagy plays an important role in the interaction between viruses and host cells.SARS-CoV-2 infection can disrupt the autophagy process in target cells.However,the precise molecular mechanism is still unknown.In this study,we discovered that the Nsp8 of SARS-CoV-2 could cause an increasing accumulation of autophagosomes by preventing the fusion of autophagosomes and lysosomes.From further investigation,we found that Nsp8 was present on mitochondria and can damage mitochondria to initiate mitophagy.The results of experiments with immunofluorescence revealed that Nsp8 induced incomplete mitophagy.Moreover,both domains of Nsp8 orchestrated their function during Nsp8-induced mitophagy,in which the N-terminal domain colocalized with mitochondria and the C-terminal domain induced auto/mitophagy.This novel finding expands our understanding of the function of Nsp8 in promoting mitochondrial damage and inducing incomplete mitophagy,which helps us to understand the etiology of COVID-19 as well as open up new pathways for creating SARS-CoV-2 treatment methods.
