Mitophagy is closely associated with the pathogenesis of secondary spinal cord injury.Abnormal mitophagy may contribute significantly to secondary spinal cord injury,leading to the impaired production of adenosine tri...Mitophagy is closely associated with the pathogenesis of secondary spinal cord injury.Abnormal mitophagy may contribute significantly to secondary spinal cord injury,leading to the impaired production of adenosine triphosphate,ion imbalance,the excessive production of reactive oxygen species,neuroinflammation,and neuronal cell death.Therefore,maintaining an appropriate balance of mitophagy is crucial when treating spinal cord injury,as both excessive and insufficient mitophagy can impede recovery.In this review,we summarize the pathological changes associated with spinal cord injury,the mechanisms of mitophagy,and the direct and indirect relationships between mitophagy and spinal cord injury.We also consider therapeutic approaches that target mitophagy for the treatment of spinal cord injury,including ongoing clinical trials and other innovative therapies,such as use of stem cells,nanomaterials,and small molecule polymers.Finally,we highlight the current challenges facing this field and suggest potential directions for future research.The aim of our review is to provide a theoretical reference for future studies targeting mitophagy in the treatment of spinal cord injury.展开更多
Spinal cord ischemia-reperfusion injury,a severe form of spinal cord damage,can lead to sensory and motor dysfunction.This injury often occurs after traumatic events,spinal cord surgeries,or thoracoabdominal aortic su...Spinal cord ischemia-reperfusion injury,a severe form of spinal cord damage,can lead to sensory and motor dysfunction.This injury often occurs after traumatic events,spinal cord surgeries,or thoracoabdominal aortic surgeries.The unpredictable nature of this condition,combined with limited treatment options,poses a significant burden on patients,their families,and society.Spinal cord ischemia-reperfusion injury leads to reduced neuronal regenerative capacity and complex pathological processes.In contrast,mitophagy is crucial for degrading damaged mitochondria,thereby supporting neuronal metabolism and energy supply.However,while moderate mitophagy can be beneficial in the context of spinal cord ischemia-reperfusion injury,excessive mitophagy may be detrimental.Therefore,this review aims to investigate the potential mechanisms and regulators of mitophagy involved in the pathological processes of spinal cord ischemia-reperfusion injury.The goal is to provide a comprehensive understanding of recent advancements in mitophagy related to spinal cord ischemia-reperfusion injury and clarify its potential clinical applications.展开更多
Elaidic acid(EA)is a typical trans fatty acid(TFA)that emerges during the processing of various fatty foods.In this study,we found that EA induced renal injury with necroptosis.Pretreatment with a reactive oxygen spec...Elaidic acid(EA)is a typical trans fatty acid(TFA)that emerges during the processing of various fatty foods.In this study,we found that EA induced renal injury with necroptosis.Pretreatment with a reactive oxygen species(ROS)inhibitor and a RIPK3 inhibitor alleviated EA-induced necroptosis.The data indicated that EA induced renal necroptosis through ROS/RIPK3/MLKL pathway.In mechanistic studies,we explored how EA induced ROS production.Results indicated that EA caused mitochondrial damage by testing MMP,MFN1,VDAC,and FIS1.Further,EA suppressed mitophagy by testing the levels of LC3,p62,PINK1,Parkin,colocalization of LC3 and Mito-Tracker Red.Mitophagy is a process of selective degradation of damaged mitochondria.A large number of damaged mitochondria couldn't be cleared by mitophagy in time,which increased ROS levels in renal cells.Pretreatment with a mitophagy activator decreased EA-induced ROS levels and mitochondrial damage.Taken together,our data identified that EA induced renal necroptosis by destroying mitochondria and inhibiting mitophagy,thereby activating the ROS/RIPK3/MLKL pathway.展开更多
Objective:To investigate the protective effects of gypenoside XVII(GP-17)against cisplatin-induced acute kidney injury and to elucidate whether its mechanism involves the activation of PINK1/Parkin-mediated mitophagy....Objective:To investigate the protective effects of gypenoside XVII(GP-17)against cisplatin-induced acute kidney injury and to elucidate whether its mechanism involves the activation of PINK1/Parkin-mediated mitophagy.Methods:Sprague-Dawley rats were randomly divided into four groups:control,cisplatin,cisplatin+GP-17,and GP-17 alone.Cisplatin was administered intraperitoneally at 20 mg/kg to induce acute kidney injury,while GP-17 was given orally at 40 mg/kg/day for 7 d.The levels of serum creatinine and blood urea nitrogen,superoxide dismutase activity,and malondialdehyde content were measured.Histopathological analysis and transmission electron microscopy were also performed to evaluate the effects of GP-17 on renal injury.Moreover,the expression of mitophagy-related proteins,including PINK1,Parkin,LC3,and p62,and the mRNA expression of inflammatory markers were determined by Western blot and quantitative RT-PCR assays.Furthermore,human renal tubular epithelial HK-2 cells were treated with cisplatin and GP-17,with or without PINK1 siRNA transfection.Cell viability,apoptosis,reactive oxygen species levels,mitochondrial membrane potential,and the protein expression associated with the PINK1/Parkin pathway were measured.Results:In rats with cisplatin-induced acute kidney injury,GP-17 significantly ameliorated cisplatin-induced elevations in serum creatinine and blood urea nitrogen,attenuated tubular damage and mitochondrial ultrastructural injury,and reduced oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content.GP-17 further upregulated the protein levels of PINK1,Parkin,and LC3-Ⅱ/Ⅰratio while promoting p62 degradation,indicating enhanced mitophagic flux.In HK-2 cells,GP-17(20μM)co-treatment markedly attenuated cisplatin-induced cytotoxicity,apoptosis,reactive oxygen species overproduction,and mitochondrial depolarization.However,all these protective effects of GP-17 were completely abolished upon PINK1 knockdown.Conclusions:GP-17 protects against cisplatin-induced nephrotoxicity by activating PINK1/Parkin-mediated mitophagy,which facilitates the clearance of damaged mitochondria,alleviates oxidative stress,and inhibits renal cell apoptosis.These findings identify GP-17 as a promising candidate for mitigating chemotherapy-induced acute kidney injury.展开更多
Objective Resveratrol(Res)is a promising anticancer drug against hepatocellular carcinoma(HCC),but whether its anti-HCC effects implicate mitophagy remains unclear.Therefore,we aimed to explore the specific role of Re...Objective Resveratrol(Res)is a promising anticancer drug against hepatocellular carcinoma(HCC),but whether its anti-HCC effects implicate mitophagy remains unclear.Therefore,we aimed to explore the specific role of Res in mitophagy and the related mechanisms during the treatment of HCC.Methods HepG2 cells and tumor-grafted nude mice were used to investigate the effects of low-,middle-and high-dose of Res on HCC progression and mitophagy in vitro and in vivo,respectively.A series of approaches including cell counting kit-8,flow cytometry,wound healing and transwell assays were used to evaluate tumor cell functions.Transmission electron microscopy,immunofluorescence and Western blotting analysis were used to assess mitophagy.Mitochondrial oxygen consumption rate,reactive oxygen species and membrane potential were used to reflect mitochondrial function.After disrupting the expression of metastasis-associated lung adenocarcinoma transcript 1(MALAT1),miR-143-3p,and ribonucleoside reductase M2(RRM2),the effects of the MALAT1/miR-143-3p/RRM2 axis on cell function and mitophagy under Res treatment were explored in vitro.Additionally,dual-luciferase reporter and chromatin immunoprecipitation were used to confirm interactions between target genes.Results Res significantly inhibited the proliferation and promoted apoptosis of HCC cells in vitro,while significantly suppressing tumor growth in a dose-dependent manner and inducing mitophagy and mitochondrial dysfunction in vivo.Interestingly,MALAT1 was highly expressed in HCC cells and its knockdown upregulated miR-143-3p expression in HCC cells,which subsequently inhibited RRM2 expression.Furthermore,in nude mice grafted with HCC tumors and treated with Res,the expression of MALAT1,miR-143-3p and RRM2 were altered significantly.In vitro data further supported the targeted binding relationships between MALAT1 and miR-143-3p and between miR-143-3p and RRM2.Therefore,a series of cell-based experiments were carried out to study the mechanism of the MALAT1/miR-143-3p/RRM2 axis involved in mitophagy and HCC;these experiments revealed that MALAT1 knockdown,miR-143-3p mimic and RRM silencing potentiated the antitumor effects of Res and its activation of mitophagy.Conclusion Res facilitated mitophagy in HCC and exerted anti-cancer effects by targeting the MALAT1/miR-143-3p/RRM2 axis.展开更多
The death of osteoblasts induced by glucocorticoid(GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head(SIONFH).Improving bone formation driven by ...The death of osteoblasts induced by glucocorticoid(GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head(SIONFH).Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH.Isovitexin has demonstrated antioxidant properties,but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored.In this study,we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches.展开更多
Ischemic stroke(IS)is a prevalent neurological disorder often resulting in significant disability or mortality.Resveratrol,extracted from Polygonum cuspidatum Sieb.et Zucc.(commonly known as Japanese knotweed),has bee...Ischemic stroke(IS)is a prevalent neurological disorder often resulting in significant disability or mortality.Resveratrol,extracted from Polygonum cuspidatum Sieb.et Zucc.(commonly known as Japanese knotweed),has been recognized for its potent neuroprotective properties.However,the neuroprotective efficacy of its derivative,(E)-4-(3,5-dimethoxystyryl)quinoline(RV02),against ischemic stroke remains inadequately explored.This study aimed to evaluate the protective effects of RV02 on neuronal ischemia-reperfusion injury both in vitro and in vivo.The research utilized an animal model of middle cerebral artery occlusion/reperfusion and SH-SY5Y cells subjected to oxygen-glucose deprivation and reperfusion to simulate ischemic conditions.The findings demonstrate that RV02 attenuates neuronal mitochondrial damage and scavenges reactive oxygen species(ROS)through mitophagy activation.Furthermore,Parkin knockdown was found to abolish RV02's ability to activate mitophagy and neuroprotection in vitro.These results suggest that RV02 shows promise as a neuroprotective agent,with the activation of Parkin-mediated mitophagy potentially serving as the primary mechanism underlying its neuroprotective effects.展开更多
OBJECTIVE:To investigate the potential mechanism of electroacupuncture(EA)in alleviating premature ovarian insufficiency(POI)and to provide a theoretical basis for EA treatment of POI.METHODS:For this purpose,a POI mi...OBJECTIVE:To investigate the potential mechanism of electroacupuncture(EA)in alleviating premature ovarian insufficiency(POI)and to provide a theoretical basis for EA treatment of POI.METHODS:For this purpose,a POI mice model was developed by injecting 12 mg/kg busulfan and 120 mg/kg cyclophosphamide intraperitoneally to induce POI.It was then proceeded by EA intervention at Guanyuan(CV4)acupoint on the second day following modeling.Similarly,apoptosis in ovarian granulosa cells was detected by terminal deoxynucleotidyl transferase d UTP nick end labeling staining,while enzyme-linked immunosorbent assay was employed for measuring serum folliclestimulating hormone(FSH),luteinizing hormone(LH),estrogen(E_(2)),and anti-müllerian hormone(AMH)levels.Moreover,transmission electron microscopy(TEM)was employed for examining mitochondrial morphology,while autophagy and hippo-yes-associated protein/transcriptional co-activator with postsynaptic density protein,drosophila disc large tumor suppressor,and zonula occludens-1 protein binding motif(YAP/TAZ)pathway related protein levels in ovarian tissue were detected via Western blotting.RESULTS:Analysis of serum levels of various hormones indicated that serum FSH and LH were reduced in EA compared to the POI group,while E_(2) and AMH levels were found to be elevated in EA compared to the POI group.The EA was found to inhibit apoptosis in granulosa cells in POI model mice,in addition to improved mitochondrial damage and significantly improved mitophagy.Pathway analysis revealed that EA was involved in activating the hippo-YAP/TAZ pathway,followed by reversing EA effects on granulosa cell apoptosis and mitophagy with the use of verteporfin,an autophagy and YAP-T-cell factor/enhancer of split and activator of transcription domain family member interaction inhibitor.CONCLUSIONS:EA at the Guanyuan(CV4)acupoint protected the granulosa cell by inhibiting cell apoptosis and promoting mitophagy,which was mediated by the Hippo-YAP/TAZ pathway.展开更多
Acute central nervous system injuries,including ischemic stro ke,intracerebral hemorrhage,subarachnoid hemorrhage,traumatic brain injury,and spinal co rd injury,are a major global health challenge.Identifying optimal ...Acute central nervous system injuries,including ischemic stro ke,intracerebral hemorrhage,subarachnoid hemorrhage,traumatic brain injury,and spinal co rd injury,are a major global health challenge.Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities.Mitochondria are susceptible to damage after acute central nervous system injury,and this leads to the release of toxic levels of reactive oxygen species,which induce cell death.Mitophagy,a selective form of autophagy,is crucial in eliminating redundant or damaged mitochondria during these events.Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries.In this review,we provide a comprehensive overview of the process,classification,and related mechanisms of mitophagy.We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy.In the final section of this review,we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.展开更多
BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),p...BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),particularly its effect on mitophagy,have not been fully elucidated.AIM To investigate the effects of liraglutide on cardiac damage and mitophagy in DCM rats.METHODS A high-fat diet and streptozotocin were used to induce DCM in rats.After 12 weeks of liraglutide treatment,rats underwent assessments of cardiac function,serum biochemical parameters,histological changes,apoptosis index,and protein levels.Furthermore,neonatal rat cardiomyocytes(NRCMs)were exposed to 25 mmol/L glucose plus 250μmol/L palmitate(high glucose+palmitic acid),with or without 200 nmol/L liraglutide,to investigate the effects of liraglutide on cardiomyocyte injury and the underlying mechanisms.RESULTS Liraglutide improved myocardial function and ameliorated cardiac damage in DCM rats,as indicated by reduced myocardial apoptosis,hypertrophy,and interstitial fibrosis(P<0.05).In NRCMs,Liraglutide alleviated mitochondrial morphological and functional damage as well as oxidative stress,improved mitophagic defects,and reduced cell apoptosis(P<0.05).Mechanistically,liraglutide alleviated NRCMs damage by enhancing mitophagy mediated by the adenosine monophosphate-activated protein kinase(AMPK)-Parkin signaling pathway,which was evidenced by the reversal of its effects upon compound C treatment.CONCLUSION Liraglutide exerted cardioprotective effects in DCM rats by inhibiting cardiomyocyte apoptosis and promoting mitophagy mediated by the AMPK-Parkin signaling pathway.展开更多
Renal tubular injury has emerged as a critical factor in the progression of diabetic kidney disease(DKD).Given renal tubules'high mitochondrial density and susceptibility to mitochondrial dysregulation and ferropt...Renal tubular injury has emerged as a critical factor in the progression of diabetic kidney disease(DKD).Given renal tubules'high mitochondrial density and susceptibility to mitochondrial dysregulation and ferroptosis,targeting these pathways could offer therapeutic potential.Metformin(MET),a first-line therapy for type 2 diabetes mellitus(T2DM),exerts reno-protective effects by improving mitochon-drial function and attenuating fibrosis;however,its role in regulating ferroptosis in DKD remains unclear.This study aimed to investigate the role of MET in modulating mitophagy and ferroptosis in diabetic kidneys.In diabetic mouse models,MET notably alleviated tubular injury by promoting mitophagy and reducing ferroptosis,as shown by increasing levels of phosphatase and tensin homolog(PTEN)-induced putative kinase 1(PINK1)and Parkin,while decreased levels of malondialdehyde(MDA)and iron con-tent.Mechanistically,MET downregulated the hypoxia-inducible factor-1alpha(HIF-1α)/myo-inositol oxygenase(MIOX)signaling axis in renal tubular epithelial cells(RTECs),thereby restoring mitophagy and inhibiting ferroptosis.These findings demonstrate that MET mitigates diabetic renal injury by promoting mitophagy and countering ferroptosis via suppressing the HIF-1α/MIOX pathway,high-lighting its potential as a therapeutic intervention for halting DKD progression.展开更多
Background:Diquat,a commonly employed bipyridyl herbicide,is recognized for its hepatotoxic effects attributed to the generation of reactive oxygen species.Baicalin(BAI),a flavonoid derivative,has garnered significant...Background:Diquat,a commonly employed bipyridyl herbicide,is recognized for its hepatotoxic effects attributed to the generation of reactive oxygen species.Baicalin(BAI),a flavonoid derivative,has garnered significant research interest for its hepatoprotective properties.Nevertheless,the clinical application of BAI is constrained by its limited water solubility and poor bioavailability.To address these challenges,BAI-nanoliposome(BAI-NL)has emerged as a novel drug delivery platform aimed at enhancing therapeutic outcomes.Methods:We used diquat-induced liver injury mouse model and AML12 hepatocytes to test the pro-tective effect of BAI and BAI-NL on liver inflammation,oxidative stress,and mitochondrial function.The parameters included histological,biochemical,and molecular biological analyses.Results:In the diquat-induced model,both BAI and BAI-NL exhibited effectiveness on attenuating liver inflammation.Ex vivo analyses further indicated that BAI-NL was superior to BAI in preserving mito-chondrial membrane potential,reducing oxidative stress,and modulating the phosphatase and tensin homolog-induced putative kinase 1(PINK1)/Parkin RBR E3 ubiquitin-protein ligase(Parkin)signaling pathway.These findings enhanced mitophagy and facilitated the removal of damaged mitochondria.Conclusions:BAI-NL exhibited superior hepatoprotective effects compared to free BAI,possibly by re-ducing inflammation,preserving mitochondrial homeostasis,and reinstating autophagic balance through modulation of the PINK1/Parkin signaling pathway.These outcomes indicate a groundbreaking method for addressing liver diseases and underscore the potential of nanoliposome technology in augmenting the efficacy of natural compounds.展开更多
Hepatic ischemia-reperfusion injury(IRI)is a prevalent pathophysiological phenomenon encountered during liver surgeries and transplantation,leading to hepatocyte damage and liver dysfunction,which significantly affect...Hepatic ischemia-reperfusion injury(IRI)is a prevalent pathophysiological phenomenon encountered during liver surgeries and transplantation,leading to hepatocyte damage and liver dysfunction,which significantly affects patient prognosis.In recent years,the role of mitophagy in hepatic IRI has garnered considerable attention.Mitochondria,known as the“powerhouses”of the cell,are crucial for maintaining normal cellular physiological functions.During the ischemia-reperfusion process,mitochondria are susceptible to damage,generating excessive harmful substances,such as reactive oxygen species(ROS),which further exacerbate cellular injury.Mitophagy is a selective cellular self-protection mechanism that maintains the quality and quantity balance of mitochondria within cells by clearing damaged or dysfunctional mitochondria.In the context of liver IRI,the activation of mitophagy is of significant importance.On one hand,mitophagy can rapidly remove damaged mitochondria,thereby reducing the release of harmful products and alleviating oxidative stress and cellular damage.Research has indicated that under ischemia-reperfusion conditions,mitophagy-related pathways are activated,promoting the clearance of damaged mitochondria.On the other hand,mitophagy also regulates cellular energy metabolism,providing essential energy support for cells under stress.With the continuous advancement of research,the understanding of the role of mitophagy in hepatic IRI has become increasingly clear.Numerous studies are dedicated to exploring the specific molecular mechanisms of mitophagy and its regulation,aiming to develop new therapeutic strategies to alleviate hepatic IRI.Although studies have demonstrated that mitophagy has a protective effect in hepatic ischemia-reperfusion injury,many issues still require further investigation.First,it is essential to further elucidate the mechanisms underlying the role of mitophagy in ischemia-reperfusion.Additionally,understanding how to mitigate liver ischemia-reperfusion injury through the modulation of mitophagy represents a key focus for future research.Future studies may encompass drug development,gene therapy,and cell therapy approaches aimed at improving the prognosis of patients affected by liver ischemia-reperfusion.展开更多
Mitochondria are crucial organelles responsible for maintaining cell growth,and their homeostasis is closely linked to p H regulation.Physiologically,mitochondria exhibit a weakly alkaline state(pH~8.0).However,when s...Mitochondria are crucial organelles responsible for maintaining cell growth,and their homeostasis is closely linked to p H regulation.Physiologically,mitochondria exhibit a weakly alkaline state(pH~8.0).However,when subjected to stress stimuli that cause damage,cells initiate the process of mitophagy,resulting in mitochondrial acidification.Therefore,monitoring changes in mitochondrial p H to comprehend the physiological processes associated with mitophagy is essential.In this study,we developed an asymmetric pentamethine cyanine dye Cy5.5-H-Cy N as a probe for continuous monitoring of mitophagy in living cells.By incorporating an azaindole structure into the dye molecule,a ratiometric fluorescence response was achieved that is specifically responsive to p H variations while preserving its ability to target mitochondria and emit near-infrared fluorescence.Through various methods inducing mitophagy,Cy5.5-H-Cy N was employed to determine mitochondrial p H quantitatively,demonstrating its suitability as an ideal probe for continuous monitoring of mitophagy in living cells.展开更多
Sirtuin 3(SIRT3)is a primary mitochondrial deacetylase.Studies have confirmed that it directly activates mitophagy by modulating mitochondrial protein acetylation.As a key homeostatic mechanism,mitophagy activation al...Sirtuin 3(SIRT3)is a primary mitochondrial deacetylase.Studies have confirmed that it directly activates mitophagy by modulating mitochondrial protein acetylation.As a key homeostatic mechanism,mitophagy activation alleviates oxidative stress-induced imbalance between cell proliferation and apoptosis,corrects stress-driven mitochondrial metabolic dysfunction,and thus inhibits excessive tumor growth,exerting significant antitumor effects.These functions establish SIRT3 as a key target for regulating mitophagy and cancer therapy.Clinically,strategies centered on its precise regulation may offer a novel direction for gastric cancer(GC)prevention and treatment,with selective activation remaining a critical challenge.SIRT3 could also serve as an auxiliary indicator in clinical guidelines for assessing tumor progression.Given this potential,this minireview systematically examines SIRT3’s mechanisms in regulating mitophagy,its role in GC pathogenesis,and translational prospects for targeting SIRT3 in GC management.展开更多
GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte ...GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.展开更多
Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study...Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.展开更多
Diabetic foot ulcer(DFU)is an increasing global burden due to the rising prevalence of diabetes,and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment.In thi...Diabetic foot ulcer(DFU)is an increasing global burden due to the rising prevalence of diabetes,and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment.In this study,naringenin(NAR)was found to accelerate diabetic wound healing in diabetic C57BL/6J wild-type(WT)mice by reducing oxidative stress,as assessed through histological assay.NAR also alleviated the inhibition of proliferation,inflammation,cell senescence,and apoptosis in HaCaT cells induced by high glucose(HG).Mechanistically,the beneficial effects of NAR on wound healing are dependent on the E3 ubiquitin-protein ligase parkin(Parkin/PRKN/Prkn).NAR upregulated the expression level of Parkin and promoted its mitochondrial translocation,thereby activating Parkin-mediated mitophagy and maintaining mitochondrial quality control(MQC).Moreover,the wound healingpromoting effects of NAR were significantly diminished in Parkin knockdown HaCaT cells and Prkn knockout(Prkn^(-/-))DFU mice.Inhibition of NAR binding to estrogen receptors(ERs)using tamoxifen(TAM)abolished the protective effects of NAR in HG-induced HaCaT cells.The luciferase reporter assay confirmed that NAR enhanced ERs binding to the estrogen response element(ERE),thereby upregulating Parkin transcription.Additionally,the cellular thermal shift assay(CETSA)revealed that NAR specifically bound to ERa.In conclusion,NAR promoted DFU wound healing by enhancing Parkin-mediated mitophagy via binding to ERa,highlighting its potential as a promising therapeutic candidate.展开更多
Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues.Dimethyl fumarate(DMF)has been used in the treatment of various immune-inflammat...Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues.Dimethyl fumarate(DMF)has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions.Here,we investigated for the first time the therapeutic effect of DMF on periodontitis.In vivo studies showed that DMF significantly inhibited periodontal destruction,enhanced mitophagy,and decreased the M1/M2 macrophage ratio.In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages,with improved mitochondrial function,inhibited oxidative stress,and increased mitophagy in RAW 264.7 cells.Furthermore,DMF increased intracellular mitochondrial Tu translation elongation factor(TUFM)levels to maintain mitochondrial homeostasis,promoted mitophagy,and modulated macrophage polarization,whereas TUFM knockdown decreased the protective effect of DMF.Finally,mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway.Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages,resulting in a shift in the balance of macrophage polarization,thereby attenuating periodontitis.Importantly,this study provides new insights into the prevention of periodontitis.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82371389,82071382(to MZ)the Priority Academic Program Development of Jiangsu Higher Education Institutions,PAPD(to MZ)+4 种基金Jiangsu Maternal and Child Health Research Key Project,No.F202013(to HS)Jiangsu 333 High Level Talent Training Project,2022(to HS)Gusu District Health Talent Training Project,No.2024145(to HS)Suzhou BenQ Medical Center Project,No.H220918(to MZ)Undergraduate Training Program for Innovation and Entrepreneurship,Soochow University,No.202410285091Z(to MZ)。
文摘Mitophagy is closely associated with the pathogenesis of secondary spinal cord injury.Abnormal mitophagy may contribute significantly to secondary spinal cord injury,leading to the impaired production of adenosine triphosphate,ion imbalance,the excessive production of reactive oxygen species,neuroinflammation,and neuronal cell death.Therefore,maintaining an appropriate balance of mitophagy is crucial when treating spinal cord injury,as both excessive and insufficient mitophagy can impede recovery.In this review,we summarize the pathological changes associated with spinal cord injury,the mechanisms of mitophagy,and the direct and indirect relationships between mitophagy and spinal cord injury.We also consider therapeutic approaches that target mitophagy for the treatment of spinal cord injury,including ongoing clinical trials and other innovative therapies,such as use of stem cells,nanomaterials,and small molecule polymers.Finally,we highlight the current challenges facing this field and suggest potential directions for future research.The aim of our review is to provide a theoretical reference for future studies targeting mitophagy in the treatment of spinal cord injury.
基金supported by Cuiying Scientific and Technological Innovation Program of Second Hospital of Lanzhou University,Nos.CY2023-QN-B18(to YD),2020QN-16(to YZ)the Natural Science Foundation of Gansu Province,No.22JR11RA082(to YZ)Key R&D Plan of Gansu Provincial Department of Science and Technology-Social Development Projects,No.23YFFA0043(to XK).
文摘Spinal cord ischemia-reperfusion injury,a severe form of spinal cord damage,can lead to sensory and motor dysfunction.This injury often occurs after traumatic events,spinal cord surgeries,or thoracoabdominal aortic surgeries.The unpredictable nature of this condition,combined with limited treatment options,poses a significant burden on patients,their families,and society.Spinal cord ischemia-reperfusion injury leads to reduced neuronal regenerative capacity and complex pathological processes.In contrast,mitophagy is crucial for degrading damaged mitochondria,thereby supporting neuronal metabolism and energy supply.However,while moderate mitophagy can be beneficial in the context of spinal cord ischemia-reperfusion injury,excessive mitophagy may be detrimental.Therefore,this review aims to investigate the potential mechanisms and regulators of mitophagy involved in the pathological processes of spinal cord ischemia-reperfusion injury.The goal is to provide a comprehensive understanding of recent advancements in mitophagy related to spinal cord ischemia-reperfusion injury and clarify its potential clinical applications.
基金supported by National Key Research and Development Program of China(2023YFD1800902).
文摘Elaidic acid(EA)is a typical trans fatty acid(TFA)that emerges during the processing of various fatty foods.In this study,we found that EA induced renal injury with necroptosis.Pretreatment with a reactive oxygen species(ROS)inhibitor and a RIPK3 inhibitor alleviated EA-induced necroptosis.The data indicated that EA induced renal necroptosis through ROS/RIPK3/MLKL pathway.In mechanistic studies,we explored how EA induced ROS production.Results indicated that EA caused mitochondrial damage by testing MMP,MFN1,VDAC,and FIS1.Further,EA suppressed mitophagy by testing the levels of LC3,p62,PINK1,Parkin,colocalization of LC3 and Mito-Tracker Red.Mitophagy is a process of selective degradation of damaged mitochondria.A large number of damaged mitochondria couldn't be cleared by mitophagy in time,which increased ROS levels in renal cells.Pretreatment with a mitophagy activator decreased EA-induced ROS levels and mitochondrial damage.Taken together,our data identified that EA induced renal necroptosis by destroying mitochondria and inhibiting mitophagy,thereby activating the ROS/RIPK3/MLKL pathway.
基金supported by grants from the Health Commission of Zigong High-Level Talent Development Project(WJW-GCCRC007).
文摘Objective:To investigate the protective effects of gypenoside XVII(GP-17)against cisplatin-induced acute kidney injury and to elucidate whether its mechanism involves the activation of PINK1/Parkin-mediated mitophagy.Methods:Sprague-Dawley rats were randomly divided into four groups:control,cisplatin,cisplatin+GP-17,and GP-17 alone.Cisplatin was administered intraperitoneally at 20 mg/kg to induce acute kidney injury,while GP-17 was given orally at 40 mg/kg/day for 7 d.The levels of serum creatinine and blood urea nitrogen,superoxide dismutase activity,and malondialdehyde content were measured.Histopathological analysis and transmission electron microscopy were also performed to evaluate the effects of GP-17 on renal injury.Moreover,the expression of mitophagy-related proteins,including PINK1,Parkin,LC3,and p62,and the mRNA expression of inflammatory markers were determined by Western blot and quantitative RT-PCR assays.Furthermore,human renal tubular epithelial HK-2 cells were treated with cisplatin and GP-17,with or without PINK1 siRNA transfection.Cell viability,apoptosis,reactive oxygen species levels,mitochondrial membrane potential,and the protein expression associated with the PINK1/Parkin pathway were measured.Results:In rats with cisplatin-induced acute kidney injury,GP-17 significantly ameliorated cisplatin-induced elevations in serum creatinine and blood urea nitrogen,attenuated tubular damage and mitochondrial ultrastructural injury,and reduced oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content.GP-17 further upregulated the protein levels of PINK1,Parkin,and LC3-Ⅱ/Ⅰratio while promoting p62 degradation,indicating enhanced mitophagic flux.In HK-2 cells,GP-17(20μM)co-treatment markedly attenuated cisplatin-induced cytotoxicity,apoptosis,reactive oxygen species overproduction,and mitochondrial depolarization.However,all these protective effects of GP-17 were completely abolished upon PINK1 knockdown.Conclusions:GP-17 protects against cisplatin-induced nephrotoxicity by activating PINK1/Parkin-mediated mitophagy,which facilitates the clearance of damaged mitochondria,alleviates oxidative stress,and inhibits renal cell apoptosis.These findings identify GP-17 as a promising candidate for mitigating chemotherapy-induced acute kidney injury.
基金supported by the Zhejiang Provincial Science and Technology Department Key Research and Development Plan(No.2020C03046).
文摘Objective Resveratrol(Res)is a promising anticancer drug against hepatocellular carcinoma(HCC),but whether its anti-HCC effects implicate mitophagy remains unclear.Therefore,we aimed to explore the specific role of Res in mitophagy and the related mechanisms during the treatment of HCC.Methods HepG2 cells and tumor-grafted nude mice were used to investigate the effects of low-,middle-and high-dose of Res on HCC progression and mitophagy in vitro and in vivo,respectively.A series of approaches including cell counting kit-8,flow cytometry,wound healing and transwell assays were used to evaluate tumor cell functions.Transmission electron microscopy,immunofluorescence and Western blotting analysis were used to assess mitophagy.Mitochondrial oxygen consumption rate,reactive oxygen species and membrane potential were used to reflect mitochondrial function.After disrupting the expression of metastasis-associated lung adenocarcinoma transcript 1(MALAT1),miR-143-3p,and ribonucleoside reductase M2(RRM2),the effects of the MALAT1/miR-143-3p/RRM2 axis on cell function and mitophagy under Res treatment were explored in vitro.Additionally,dual-luciferase reporter and chromatin immunoprecipitation were used to confirm interactions between target genes.Results Res significantly inhibited the proliferation and promoted apoptosis of HCC cells in vitro,while significantly suppressing tumor growth in a dose-dependent manner and inducing mitophagy and mitochondrial dysfunction in vivo.Interestingly,MALAT1 was highly expressed in HCC cells and its knockdown upregulated miR-143-3p expression in HCC cells,which subsequently inhibited RRM2 expression.Furthermore,in nude mice grafted with HCC tumors and treated with Res,the expression of MALAT1,miR-143-3p and RRM2 were altered significantly.In vitro data further supported the targeted binding relationships between MALAT1 and miR-143-3p and between miR-143-3p and RRM2.Therefore,a series of cell-based experiments were carried out to study the mechanism of the MALAT1/miR-143-3p/RRM2 axis involved in mitophagy and HCC;these experiments revealed that MALAT1 knockdown,miR-143-3p mimic and RRM silencing potentiated the antitumor effects of Res and its activation of mitophagy.Conclusion Res facilitated mitophagy in HCC and exerted anti-cancer effects by targeting the MALAT1/miR-143-3p/RRM2 axis.
基金supported by the National Natural Science Foundation of China(Grant Nos:82374475 and 82104883,China).
文摘The death of osteoblasts induced by glucocorticoid(GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head(SIONFH).Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH.Isovitexin has demonstrated antioxidant properties,but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored.In this study,we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches.
基金supported by the National Natural ScienceFoundation of China (No.82174076)the Construction Project of Liaoning Provincial Key Laboratory,China (No.2022JH13/10200026)+2 种基金the Fundamental Research Funds for the Central Universities (No.N2220002)the 111 Project (No.B16009)the Research Project of Educational Commission of Liaoning Province (No.LJ212410164003)。
文摘Ischemic stroke(IS)is a prevalent neurological disorder often resulting in significant disability or mortality.Resveratrol,extracted from Polygonum cuspidatum Sieb.et Zucc.(commonly known as Japanese knotweed),has been recognized for its potent neuroprotective properties.However,the neuroprotective efficacy of its derivative,(E)-4-(3,5-dimethoxystyryl)quinoline(RV02),against ischemic stroke remains inadequately explored.This study aimed to evaluate the protective effects of RV02 on neuronal ischemia-reperfusion injury both in vitro and in vivo.The research utilized an animal model of middle cerebral artery occlusion/reperfusion and SH-SY5Y cells subjected to oxygen-glucose deprivation and reperfusion to simulate ischemic conditions.The findings demonstrate that RV02 attenuates neuronal mitochondrial damage and scavenges reactive oxygen species(ROS)through mitophagy activation.Furthermore,Parkin knockdown was found to abolish RV02's ability to activate mitophagy and neuroprotection in vitro.These results suggest that RV02 shows promise as a neuroprotective agent,with the activation of Parkin-mediated mitophagy potentially serving as the primary mechanism underlying its neuroprotective effects.
基金Shenzhen Science and Innovation Commission:Investigating the Mechanism of Action of Acupuncture in Regulating the Gut Microbiome to Inhibit Apoptosis of Ovarian Granulosa Cells in Premature Ovarian Insufficiency Mice based on the Rictor/Torepamycin Target Protein c2 Pathway(No.JCYJ20210324130001004)Sanming Project of Medicine in Shenzhen:the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine,Luo Songping National Famous Chinese Medicine Practitioner Female Reproductive Disorders Prevention and Treatment Team(SZZYSM202311010)。
文摘OBJECTIVE:To investigate the potential mechanism of electroacupuncture(EA)in alleviating premature ovarian insufficiency(POI)and to provide a theoretical basis for EA treatment of POI.METHODS:For this purpose,a POI mice model was developed by injecting 12 mg/kg busulfan and 120 mg/kg cyclophosphamide intraperitoneally to induce POI.It was then proceeded by EA intervention at Guanyuan(CV4)acupoint on the second day following modeling.Similarly,apoptosis in ovarian granulosa cells was detected by terminal deoxynucleotidyl transferase d UTP nick end labeling staining,while enzyme-linked immunosorbent assay was employed for measuring serum folliclestimulating hormone(FSH),luteinizing hormone(LH),estrogen(E_(2)),and anti-müllerian hormone(AMH)levels.Moreover,transmission electron microscopy(TEM)was employed for examining mitochondrial morphology,while autophagy and hippo-yes-associated protein/transcriptional co-activator with postsynaptic density protein,drosophila disc large tumor suppressor,and zonula occludens-1 protein binding motif(YAP/TAZ)pathway related protein levels in ovarian tissue were detected via Western blotting.RESULTS:Analysis of serum levels of various hormones indicated that serum FSH and LH were reduced in EA compared to the POI group,while E_(2) and AMH levels were found to be elevated in EA compared to the POI group.The EA was found to inhibit apoptosis in granulosa cells in POI model mice,in addition to improved mitochondrial damage and significantly improved mitophagy.Pathway analysis revealed that EA was involved in activating the hippo-YAP/TAZ pathway,followed by reversing EA effects on granulosa cell apoptosis and mitophagy with the use of verteporfin,an autophagy and YAP-T-cell factor/enhancer of split and activator of transcription domain family member interaction inhibitor.CONCLUSIONS:EA at the Guanyuan(CV4)acupoint protected the granulosa cell by inhibiting cell apoptosis and promoting mitophagy,which was mediated by the Hippo-YAP/TAZ pathway.
基金supported by the National Natural Science Foundation of China,Nos.81920108017(to YX),82130036(to YX),82371326(to XC),82171310(to XC)the STI2030-Major Projects,No.2022ZD0211800(to YX)Jiangsu Province Key Medical Discipline,No.ZDXK202216(to YX)。
文摘Acute central nervous system injuries,including ischemic stro ke,intracerebral hemorrhage,subarachnoid hemorrhage,traumatic brain injury,and spinal co rd injury,are a major global health challenge.Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities.Mitochondria are susceptible to damage after acute central nervous system injury,and this leads to the release of toxic levels of reactive oxygen species,which induce cell death.Mitophagy,a selective form of autophagy,is crucial in eliminating redundant or damaged mitochondria during these events.Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries.In this review,we provide a comprehensive overview of the process,classification,and related mechanisms of mitophagy.We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy.In the final section of this review,we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.
基金Supported by National Natural Science Foundation of China,No.81370221 and No.82172334PUMC Youth Fund,No.3332018200+1 种基金National Science and Technology Major Project of the Ministry of Science and Technology of China,No.2024ZD0522005CAMS Innovation Fund for Medical Science,No.2016-CXGC05-4 and No.2021-I2M-1-008.
文摘BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),particularly its effect on mitophagy,have not been fully elucidated.AIM To investigate the effects of liraglutide on cardiac damage and mitophagy in DCM rats.METHODS A high-fat diet and streptozotocin were used to induce DCM in rats.After 12 weeks of liraglutide treatment,rats underwent assessments of cardiac function,serum biochemical parameters,histological changes,apoptosis index,and protein levels.Furthermore,neonatal rat cardiomyocytes(NRCMs)were exposed to 25 mmol/L glucose plus 250μmol/L palmitate(high glucose+palmitic acid),with or without 200 nmol/L liraglutide,to investigate the effects of liraglutide on cardiomyocyte injury and the underlying mechanisms.RESULTS Liraglutide improved myocardial function and ameliorated cardiac damage in DCM rats,as indicated by reduced myocardial apoptosis,hypertrophy,and interstitial fibrosis(P<0.05).In NRCMs,Liraglutide alleviated mitochondrial morphological and functional damage as well as oxidative stress,improved mitophagic defects,and reduced cell apoptosis(P<0.05).Mechanistically,liraglutide alleviated NRCMs damage by enhancing mitophagy mediated by the adenosine monophosphate-activated protein kinase(AMPK)-Parkin signaling pathway,which was evidenced by the reversal of its effects upon compound C treatment.CONCLUSION Liraglutide exerted cardioprotective effects in DCM rats by inhibiting cardiomyocyte apoptosis and promoting mitophagy mediated by the AMPK-Parkin signaling pathway.
基金BioRender.com for the picture drawingEditage(www.editage.cn)for English language editing+2 种基金the Natural Science Foundation of Henan Province(Grant No.:252300421361)the National Natural Science Foundation of China(Grant No.:82000787)the Henan Medical Science and TechnologyResearch Program Project(Grant No.:SBGJ202102142).
文摘Renal tubular injury has emerged as a critical factor in the progression of diabetic kidney disease(DKD).Given renal tubules'high mitochondrial density and susceptibility to mitochondrial dysregulation and ferroptosis,targeting these pathways could offer therapeutic potential.Metformin(MET),a first-line therapy for type 2 diabetes mellitus(T2DM),exerts reno-protective effects by improving mitochon-drial function and attenuating fibrosis;however,its role in regulating ferroptosis in DKD remains unclear.This study aimed to investigate the role of MET in modulating mitophagy and ferroptosis in diabetic kidneys.In diabetic mouse models,MET notably alleviated tubular injury by promoting mitophagy and reducing ferroptosis,as shown by increasing levels of phosphatase and tensin homolog(PTEN)-induced putative kinase 1(PINK1)and Parkin,while decreased levels of malondialdehyde(MDA)and iron con-tent.Mechanistically,MET downregulated the hypoxia-inducible factor-1alpha(HIF-1α)/myo-inositol oxygenase(MIOX)signaling axis in renal tubular epithelial cells(RTECs),thereby restoring mitophagy and inhibiting ferroptosis.These findings demonstrate that MET mitigates diabetic renal injury by promoting mitophagy and countering ferroptosis via suppressing the HIF-1α/MIOX pathway,high-lighting its potential as a therapeutic intervention for halting DKD progression.
基金supported by grants from the National Key Re-search and Development Program of China(2023YFC3603100 and 2023YFC3603105)“Leading Goose”R&D Program of Zhejiang Province(2022C03076-4).
文摘Background:Diquat,a commonly employed bipyridyl herbicide,is recognized for its hepatotoxic effects attributed to the generation of reactive oxygen species.Baicalin(BAI),a flavonoid derivative,has garnered significant research interest for its hepatoprotective properties.Nevertheless,the clinical application of BAI is constrained by its limited water solubility and poor bioavailability.To address these challenges,BAI-nanoliposome(BAI-NL)has emerged as a novel drug delivery platform aimed at enhancing therapeutic outcomes.Methods:We used diquat-induced liver injury mouse model and AML12 hepatocytes to test the pro-tective effect of BAI and BAI-NL on liver inflammation,oxidative stress,and mitochondrial function.The parameters included histological,biochemical,and molecular biological analyses.Results:In the diquat-induced model,both BAI and BAI-NL exhibited effectiveness on attenuating liver inflammation.Ex vivo analyses further indicated that BAI-NL was superior to BAI in preserving mito-chondrial membrane potential,reducing oxidative stress,and modulating the phosphatase and tensin homolog-induced putative kinase 1(PINK1)/Parkin RBR E3 ubiquitin-protein ligase(Parkin)signaling pathway.These findings enhanced mitophagy and facilitated the removal of damaged mitochondria.Conclusions:BAI-NL exhibited superior hepatoprotective effects compared to free BAI,possibly by re-ducing inflammation,preserving mitochondrial homeostasis,and reinstating autophagic balance through modulation of the PINK1/Parkin signaling pathway.These outcomes indicate a groundbreaking method for addressing liver diseases and underscore the potential of nanoliposome technology in augmenting the efficacy of natural compounds.
文摘Hepatic ischemia-reperfusion injury(IRI)is a prevalent pathophysiological phenomenon encountered during liver surgeries and transplantation,leading to hepatocyte damage and liver dysfunction,which significantly affects patient prognosis.In recent years,the role of mitophagy in hepatic IRI has garnered considerable attention.Mitochondria,known as the“powerhouses”of the cell,are crucial for maintaining normal cellular physiological functions.During the ischemia-reperfusion process,mitochondria are susceptible to damage,generating excessive harmful substances,such as reactive oxygen species(ROS),which further exacerbate cellular injury.Mitophagy is a selective cellular self-protection mechanism that maintains the quality and quantity balance of mitochondria within cells by clearing damaged or dysfunctional mitochondria.In the context of liver IRI,the activation of mitophagy is of significant importance.On one hand,mitophagy can rapidly remove damaged mitochondria,thereby reducing the release of harmful products and alleviating oxidative stress and cellular damage.Research has indicated that under ischemia-reperfusion conditions,mitophagy-related pathways are activated,promoting the clearance of damaged mitochondria.On the other hand,mitophagy also regulates cellular energy metabolism,providing essential energy support for cells under stress.With the continuous advancement of research,the understanding of the role of mitophagy in hepatic IRI has become increasingly clear.Numerous studies are dedicated to exploring the specific molecular mechanisms of mitophagy and its regulation,aiming to develop new therapeutic strategies to alleviate hepatic IRI.Although studies have demonstrated that mitophagy has a protective effect in hepatic ischemia-reperfusion injury,many issues still require further investigation.First,it is essential to further elucidate the mechanisms underlying the role of mitophagy in ischemia-reperfusion.Additionally,understanding how to mitigate liver ischemia-reperfusion injury through the modulation of mitophagy represents a key focus for future research.Future studies may encompass drug development,gene therapy,and cell therapy approaches aimed at improving the prognosis of patients affected by liver ischemia-reperfusion.
基金supported by the Fundamental Research Funds for the Central Universities(Nos.DUT23YG137 and DUT22LAB601)Liaoning Binhai Laboratory(No.LBLB-202303)+1 种基金Liaoning Province Science and Technology Joint Fund(Nos.2023JH2/101800039 and 2023JH2/101800037)National Natural Science Foundation of China(Nos.21925802,22090011,and 21878039)。
文摘Mitochondria are crucial organelles responsible for maintaining cell growth,and their homeostasis is closely linked to p H regulation.Physiologically,mitochondria exhibit a weakly alkaline state(pH~8.0).However,when subjected to stress stimuli that cause damage,cells initiate the process of mitophagy,resulting in mitochondrial acidification.Therefore,monitoring changes in mitochondrial p H to comprehend the physiological processes associated with mitophagy is essential.In this study,we developed an asymmetric pentamethine cyanine dye Cy5.5-H-Cy N as a probe for continuous monitoring of mitophagy in living cells.By incorporating an azaindole structure into the dye molecule,a ratiometric fluorescence response was achieved that is specifically responsive to p H variations while preserving its ability to target mitochondria and emit near-infrared fluorescence.Through various methods inducing mitophagy,Cy5.5-H-Cy N was employed to determine mitochondrial p H quantitatively,demonstrating its suitability as an ideal probe for continuous monitoring of mitophagy in living cells.
文摘Sirtuin 3(SIRT3)is a primary mitochondrial deacetylase.Studies have confirmed that it directly activates mitophagy by modulating mitochondrial protein acetylation.As a key homeostatic mechanism,mitophagy activation alleviates oxidative stress-induced imbalance between cell proliferation and apoptosis,corrects stress-driven mitochondrial metabolic dysfunction,and thus inhibits excessive tumor growth,exerting significant antitumor effects.These functions establish SIRT3 as a key target for regulating mitophagy and cancer therapy.Clinically,strategies centered on its precise regulation may offer a novel direction for gastric cancer(GC)prevention and treatment,with selective activation remaining a critical challenge.SIRT3 could also serve as an auxiliary indicator in clinical guidelines for assessing tumor progression.Given this potential,this minireview systematically examines SIRT3’s mechanisms in regulating mitophagy,its role in GC pathogenesis,and translational prospects for targeting SIRT3 in GC management.
基金Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education,No.NRF-2022R1I1A1A01068652.
文摘GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.
基金funded by National Key R&D Program of China(2024YFD2402000)。
文摘Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.
基金supported by the National Natural Science Foundation of China(Grant Nos.82270613 and 82170844)the open fund of Metabolic Vascular Diseases Key Laboratory of Sichuan Province,China(Grant Nos.:2022MVDKL-G3 and 2022MVDKL-G4).
文摘Diabetic foot ulcer(DFU)is an increasing global burden due to the rising prevalence of diabetes,and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment.In this study,naringenin(NAR)was found to accelerate diabetic wound healing in diabetic C57BL/6J wild-type(WT)mice by reducing oxidative stress,as assessed through histological assay.NAR also alleviated the inhibition of proliferation,inflammation,cell senescence,and apoptosis in HaCaT cells induced by high glucose(HG).Mechanistically,the beneficial effects of NAR on wound healing are dependent on the E3 ubiquitin-protein ligase parkin(Parkin/PRKN/Prkn).NAR upregulated the expression level of Parkin and promoted its mitochondrial translocation,thereby activating Parkin-mediated mitophagy and maintaining mitochondrial quality control(MQC).Moreover,the wound healingpromoting effects of NAR were significantly diminished in Parkin knockdown HaCaT cells and Prkn knockout(Prkn^(-/-))DFU mice.Inhibition of NAR binding to estrogen receptors(ERs)using tamoxifen(TAM)abolished the protective effects of NAR in HG-induced HaCaT cells.The luciferase reporter assay confirmed that NAR enhanced ERs binding to the estrogen response element(ERE),thereby upregulating Parkin transcription.Additionally,the cellular thermal shift assay(CETSA)revealed that NAR specifically bound to ERa.In conclusion,NAR promoted DFU wound healing by enhancing Parkin-mediated mitophagy via binding to ERa,highlighting its potential as a promising therapeutic candidate.
基金Natural Science Foundation of China(grant nos.82270991)Zhejiang Provincial Natural Science Foundation of China/Outstanding Youth Science Foundation(grant no.LR21H140002)+4 种基金Medical Health Science and Technology Major Project of Zhejiang Provincial Health Commission(grant no.WKJ-ZJ-2311)Wenzhou Science and Technology Bureau Public Welfare Social Development(Medical and Health)Science and Technology Project(grant no.ZY2021015)Opening Research Fund from Shanghai Key Laboratory of Stomatology,Shanghai Ninth People’s Hospital,College of Stomatology,Shanghai Jiao Tong University School of Medicine(grant no.2022SKLS-KFKT011)Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research(grant no.GXKLRROM2106)State Key Laboratory of Oral Diseases Open Fund(grant no.SKLOD2024OF08).
文摘Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues.Dimethyl fumarate(DMF)has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions.Here,we investigated for the first time the therapeutic effect of DMF on periodontitis.In vivo studies showed that DMF significantly inhibited periodontal destruction,enhanced mitophagy,and decreased the M1/M2 macrophage ratio.In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages,with improved mitochondrial function,inhibited oxidative stress,and increased mitophagy in RAW 264.7 cells.Furthermore,DMF increased intracellular mitochondrial Tu translation elongation factor(TUFM)levels to maintain mitochondrial homeostasis,promoted mitophagy,and modulated macrophage polarization,whereas TUFM knockdown decreased the protective effect of DMF.Finally,mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway.Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages,resulting in a shift in the balance of macrophage polarization,thereby attenuating periodontitis.Importantly,this study provides new insights into the prevention of periodontitis.
