Modulations of mitochondrial dysfunction,which involve a series of dynamic processes such as mitochondrial biogenesis,mitochondrial fusion and fission,mitochondrial transport,mitochondrial autophagy,mitochondrial apop...Modulations of mitochondrial dysfunction,which involve a series of dynamic processes such as mitochondrial biogenesis,mitochondrial fusion and fission,mitochondrial transport,mitochondrial autophagy,mitochondrial apoptosis,and oxidative stress,play an important role in the onset and progression of stroke.With a better understanding of the critical role of mitochondrial dysfunction modulations in post-stroke neurological injury,these modulations have emerged as a potential target for stroke prevention and treatment.Additionally,since effective treatments for stroke are extremely limited and natural products currently offer some outstanding advantages,we focused on the findings and mechanisms of action related to the use of natural products for targeting mitochondrial dysfunction in the treatment of stroke.Natural products achieve neuroprotective through multi-target regulation of mitochondrial dysfunction encompassing the following processes:(1)Mitochondrial biogenesis:Cordyceps and hydroxysafflor yellow A activate the peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor pathway,promote mitochondrial DNA replication and respiratory chain protein synthesis,and thereby restore energy supply in the ischemic penumbra.(2)Mitochondrial dynamics balance:Ginsenoside Rb3 promotes Opa1-mediated neural stem cell migration and diffusion for recovery of damaged brain tissue.(3)Mitochondrial autophagy:Gypenoside XVII selectively eliminates damaged mitochondria via the phosphatase and tensin homolog-induced kinase 1/Parkin pathway and blocks reactive oxygen species and the NOD-like receptor protein 3 inflammasome cascade,thereby alleviating blood-brain barrier damage.(4)Anti-apoptotic mechanisms:Ginkgolide K inhibits Bax mitochondrial translocation and downregulates caspase-3/9 activity,reducing neuronal programmed death induced by ischemia-reperfusion.(5)Oxidative stress regulation:Scutellarin exerts antioxidant properties and improves neurological function by modulating the extracellular signal-regulated kinase 5-Kruppel-like factor 2-endothelial nitric oxide synthase signaling pathway.(6)Intercellular mitochondrial transport:Neuroprotective effects of Chrysophanol are associated with accelerated mitochondrial transfer from astrocytes to neurons.Existing studies have confirmed that natural products exhibit neuroprotective effects through multidimensional interventions targeting mitochondrial dysfunction in both ischemic and hemorrhagic stroke models.However,their clinical translation still faces challenges,such as the difficulty in standardization due to component complexity,insufficient cross-regional clinical data,and the lack of long-term safety evaluations.Future research should aim to integrate new technologies,such as single-cell sequencing and organoid models,to deeply explore the mitochondria-targeting mechanisms of natural products and validate their efficacy through multicenter clinical trials,providing theoretical support and translational pathways for the development of novel anti-stroke drugs.展开更多
Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pa...Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.展开更多
Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors,shaping the dynamic landscape of the developing brain.A major component of the developing brain that enables th...Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors,shaping the dynamic landscape of the developing brain.A major component of the developing brain that enables this dynamic is the white matter(WM),known to be affected in neurodevelopmental disorders(NDDs)(Rokach et al.,2024).WM formation is mediated by myelination,a multifactorial process driven by neuro-glia interactions dependent on proper neuronal functionality(Simons and Trajkovic,2006).Another key aspect of neurodevelopmental abnormalities involves neuronal dynamics and function,with recent advances significantly enhancing our understanding of both neuronal and glial mitochondrial function(Devine and Kittler,2018;Rojas-Charry et al.,2021).Energy homeostasis in neurons,attributed largely to mitochondrial function,is critical for proper functionality and interactions with oligodendrocytes(OLs),the cells forming myelin in the brain’s WM.We herein discuss the interplay between these processes and speculate on potential dysfunction in NDDs.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,wi...Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.展开更多
Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression...Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression Omnibus(GEO)datasets showed that ZFP36 was a differentially expressed gene(DEG)in OS.Western blot and immunohistochemistry results showed that ZFP36 was downregulated in OS tumors and cell lines.ZFP36 overexpression plasmids and small interfering RNAs(siRNAs)were respectively transfected into OS cells.ZFP36 overexpression restrained proliferation,migration,and invasion in MG63 and U2OS cells,while ZFP36 knockdown displayed the opposite results.Moreover,ZFP36 overexpression increased the levels of intracellular Fe2t,reactive oxygen species(ROS),and malondialdehyde(MDA),and decreased the levels of glutathione(GSH),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11).ZFP36 overexpression disturbed mitochondrial membrane potential(MMP)and mitochondrial morphology in OS cells.However,ZFP36 knockdown had the opposite results.Mechanistic studies indicated that ZFP36 promoted E2F transcription factor 1(E2F1)messenger RNA(mRNA)degradation by binding to the AU-rich elements(AREs)within E2F130 untranslated region(30UTR)in OS cells.E2F1 overexpression abrogated the effects of ZFP36 overexpression on malignant progression,ferroptosis,and mitochondrial dysfunction in OS cells.Furthermore,E2F1 promoted the transcription activation of activating transcription factor 4(ATF4)by binding to ATF4 promoter.E2F1 knockdown inhibited malignant progression,and promoted ferroptosis and mitochondrial dysfunction in OS cells,which was abrogated by ATF4 overexpression.Additionally,MG63 cells transfected with lentivirus ZFP36 overexpression vector(Lv-ZFP36)were injected into nude mice and tumor growth was monitored.ZFP36 overexpression significantly suppressed OS tumor growth under in vivo settings.In conclusion,ZFP36 overexpression promoted ferroptosis and mitochondrial dysfunction and inhibited malignant progression in OS by regulating the E2F1/ATF4 axis.We may provide the promising ZFP36 target for OS treatment.展开更多
Deuterium is a heavy isotope of hydrogen,with an extra neutron,endowing it with unique biophysical and biochemical properties compared to hydrogen.The ATPase pumps in the mitochondria depend upon proton motive force t...Deuterium is a heavy isotope of hydrogen,with an extra neutron,endowing it with unique biophysical and biochemical properties compared to hydrogen.The ATPase pumps in the mitochondria depend upon proton motive force to catalyze the reaction that produces ATP.Deuterons disrupt the pumps,inducing excessive reactive oxygen species and decreased ATP synthesis.The aim of this review is to develop a theory that mitochondrial dysfunction due to deuterium overload,systemically,is a primary cause of Parkinson’s disease(PD).The gut microbes supply deuterium-depleted short chain fatty acids(SCFAs)to the colonocytes,particularly butyrate,and an insufficient supply of butyrate may be a primary driver behind mitochondrial dysfunction in the gut,an early factor in PD.Indeed,low gut butyrate is a characteristic feature of PD.Mitochondrial dysfunction is a factor in many diseases,including all neurodegenerative diseases.Biological organisms have devised sophisticated strategies for protecting the ATPase pumps from deuterium overload.One such strategy may involve capturing deuterons in bis-allylic carbon atoms present in polyunsaturated fatty acids(PUFAs)in cardiolipin.Cardiolipin uniquely localizes to the inner membrane of the intermembrane space,tightly integrated into ATPase proteins.Bis-allylic carbon atoms can capture and retain deuterium,and,interestingly,deuterium doping in PUFAs can quench the chain reaction that causes massive damage upon lipid peroxidation.Neuronal cardiolipin is especially rich in docosahexaenoic acid(DHA),a PUFA with five bisallylic carbon atoms.Upon excessive oxidative stress,cardiolipin migrates to the outer membrane,where it interacts withα-synuclein(α-syn),the amyloidogenic protein that accumulates as fibrils in Lewy bodies in association with PD.Such interaction leads to pore formation and the launch of an apoptotic cascade.α-syn misfolding likely begins in the gut,and misfoldedα-syn travels along nerve fibers,particularly the vagus nerve,to reach the brainstem nuclei,where it can seed misfolding ofα-syn molecules already present there.Mitochondrial dysfunction in the gut may be a primary factor in PD,and low-deuterium nutrients may be therapeutic.展开更多
Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apo...Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis.The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA.As age advances,mitochondrial function declines progressively,which leads to an imbalance in chondrocyte energy homeostasis,partially initiating the process of cartilage degeneration.Elevated oxidative stress,impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology,with mitochondrial DNA haplogroups,particularly haplogroup J,influencing OA progression.Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases,with triphenylphosphonium(TPP)emerging as the most widely utilized molecule.Other strategies encompass Dequalinium(DQA),the Szeto-Schiller(SS)tetrapeptide family,the KLA peptide,and mitochondrial-penetrating peptides(MPP),etc.展开更多
Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and ...Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and pulmonary vascular remodeling,rise with disease severity,and may contribute to the excess cardiovascular risk—although effect sizes and causality remain uncertain.This review centers on the homocysteine–carnitine relationship in COPD pathophysiology.Carnitine deficiency,prevalent in COPD,can worsen mitochondrial bioenergetics,promote accumulation of acyl intermediates,and reduce nitric oxide bioavailability via endothelial nitric oxide synthase uncoupling(eNOS).Conversely,restoring carnitine status in experimental and early clinical settings has been associated with lower homocysteine,improved nitric oxide signaling,and attenuation of vascular remodeling,suggesting a reciprocal link rather than a one-way pathway.We review existing evidence on various COPD phenotypes and severities,delineate mechanisms that connect homocysteine,carnitine metabolism,mitochondria,redox balance and eNOS uncoupling,and evaluate therapeutic strategies—ranging from lowering homocysteine with B-group vitamins to integrated approaches that also supportmitochondrial function and redox homeostasis,including targeted carnitine supplementation.The role of L-carnitine as a potential therapeutic agent for lowering homocysteine and improving mitochondrial and vascular function warrants further investigation,as it may help slow the progression of COPD and its related comorbidities.展开更多
Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in re...Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in reduced ATP synthesis,elevated reactive oxygen species(ROS)formation,and mitochondrial malfunction,which instigates oxidative stress and cellular damage,critical elements in neurodegenerative disorders like Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Alzheimer’s disease(AD).In addition to causing direct neuronal injury,rotenone significantly contributes to the activation of glial cells,specifically microglia and astrocytes.Activated microglia assumes a proinflammatory(M1)phenotype,distinguished by the secretion of inflammatory cytokines including tumor necrosis factor alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),with the generation of nitric oxide and ROS,which exacerbate the neuronal injury.Astrocytes can intensify neuroinflammation by secreting proinflammatory molecules and impairing their neuroprotective roles.Our hypothesis is that rotenone is posited to elicit a neuroinflammatory response via mitochondrial malfunction,ROS generation,and the activation of proinflammatory pathways in microglia and astrocytes.This mechanism leads to accelerated neuronal impair-ment,promoting neurodegeneration.Comprehending the inflammatory pathways activated by rotenone is crucial for pinpointing therapeutic targets to regulate glial responses and mitigate the advancement of neurodegenerative disorders linked to mitochondrial malfunction and chronic inflammation.This review examines the function of glial cells and critical inflammatory pathways,namely Nuclear factor kappaβ(NF-κB),Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin(PI3K/AKT/mTOR),and Wnt/β-catenin signaling pathway in Parkinson’s disease,Alzheimer’s disease,and ALS,emphasizing illness-specific responses and the translational constraints of rotenone-based models.The objective is to consolidate existing understanding regarding the role of rotenone-induced mitochondrial failure in promoting glial activation and neuroinflammation,highlighting the necessity for additional research into these pathways.Despite the prevalent application of rotenone in experimental models,its specific effects on glial-mediated inflammation are inadequately comprehended,necessitating further investigation to guide the formulation of targeted therapeutic strategies.展开更多
Acute pancreatitis(AP)is a life-threatening inflammatory condition triggered by the premature activation of trypsin.The limited understanding of its underlying pathophysiology remains a key obstacle to the development...Acute pancreatitis(AP)is a life-threatening inflammatory condition triggered by the premature activation of trypsin.The limited understanding of its underlying pathophysiology remains a key obstacle to the development of targeted therapies.Mounting evidence now underscores mitochondrial dysfunction as a critical pathogenic driver in AP.Cellular mitochondrial dysfunction often precedes both cytokine release and trypsin activation,potentially serving as a primary initiator in the development and advancement of AP.Mitochondrial dysfunction is associated with calcium overload,inflammatory reactions,mitochondrial permeability transition pore opening,mitophagy damage,and other potential pathogenesis of pancreatic cell injury.Elucidating the impact of mitochondrial injury in AP may facilitate the development of innovative treatment approaches.This review provides a comprehensive and systematic analysis of the pivotal role of mitochondria in regulating pancreatic homeostasis,while evaluating emerging therapeutic strategies aimed at mitigating mitochondrial dysfunction.By integrating cuttingedge research findings,this work highlights the translational potential of these advancements in redefining diagnostic frameworks and optimizing therapeutic approaches for the management of AP.展开更多
Background:Acute Myeloid Leukemia(AML)is a highly aggressive clonal hematological malignancy with limited treatment options.This study aimed to evaluate the therapeutic potential of nigericin,a polyether ionophore der...Background:Acute Myeloid Leukemia(AML)is a highly aggressive clonal hematological malignancy with limited treatment options.This study aimed to evaluate the therapeutic potential of nigericin,a polyether ionophore derived from Streptomyces DASNCL-29,as a mitochondrial-targeted agent for AML treatment.Methods:Nigericin was isolated from Streptomyces DASNCL-29 and characterized via chromatography and NMR.Its cytotoxicity was tested in MOLM13(sensitive and venetoclax-resistant)and HL60(sensitive and cytarabine-resistant)cells using the MTT assay.Mitochondrial dysfunction was assessed by measuring reactive oxygen species(ROS),mitochondrial membrane potential(Δψm),and mitochondrial mass.Apoptosis was evaluated with Annexin V/PI assays and immunoblotting,while proteomic analysis was conducted using Liquid Chromatography-Tandem Mass Spectrometry(LC-MS/MS)to identify differentially regulated proteins.Results:Nigericin demonstrated potent cytotoxicity with IC50 values of 57.02 nM in MOLM13-sensitive,35.29 nM in MOLM13-resistant,20.49 nM in HL60-sensitive,and 1.197 nM in HL60-cytarabine-resistant cells.Apoptosis was confirmed by Annexin V/PI staining and caspase-3/PARP cleavage,along with MCL-1 downregulation.Mitochondrial dysfunction was evident from increased ROS,reducedΔψm,and decreased mitochondrial mass.Proteomic profiling identified 264 dysregulated proteins,including a 3.8-fold upregulation of Succinate Dehydrogenase[Ubiquinone]Flavoprotein Subunit A(SDHA).Conclusion:Nigericin induces apoptosis in AML cells by disrupting mitochondrial function and enhancing oxidative stress.Its nanomolar potency highlights the need for further mechanistic studies and in vivo evaluations to explore its potential in AML treatment.展开更多
Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiabl...Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiable matter(USM),a composition of highly active ingredients found in walnut oil,has demonstrated antioxidant effects.This study aims to explore the neuroprotective effects of USM on d-galactose-treated C57BL/6 mice and elucidate its underlying mechanism,which was validated in PC12 cells treated with d-galactose.The results of behavioral tests demonstrated that USM significantly improved cognitive deficits associated with aging.The morphological analysis demonstrated that USM effectively alleviated hippocampal neuronal damage,synaptic impairment,and mitochondrial dysfunction induced by d-galactose.Furthermore,USM significantly increases the antioxidant enzymes activity while reducing the malondialdehyde and reactive oxygen species levels.The results suggest that USM can mitigate age-related symptoms caused by d-galactose by activating the nuclear factor erythroid-2-related factor 2 signaling pathway,which enhances the expression of antioxidant enzymes,restore redox balance,and improves synaptic and mitochondrial functions.This has a positive on improving cognition and memory disorders in elderly mice.展开更多
Benign prostatic hyperplasia(BPH)represents a prevalent etiology of lower urinary tract symptoms(LUTS)in the male population,clinically defined by a nonmalignant proliferation of prostatic tissue.While BPH exhibits a ...Benign prostatic hyperplasia(BPH)represents a prevalent etiology of lower urinary tract symptoms(LUTS)in the male population,clinically defined by a nonmalignant proliferation of prostatic tissue.While BPH exhibits a high prevalence among older male populations globally,the precise underlying mechanisms contributing to its development remain incompletely elucidated.Mitochondria,essential organelles within eukaryotic cells,are critical for cellular bioenergetics,the regulation of reactive oxygen species(ROS)generation,and the modulation of cell death pathways.The maintenance of mitochondrial homeostasis involves a complex interplay of processes.By synthesizing previous literature,this review discusses mitochondrial homeostasis in prostate glands and the role of mitochondrial dysfunction in the context of BPH.Furthermore,the review delved into each dimension of mitochondrial dysfunction in the specific etiology of BPH,highlighting its impact on cell survival,apoptosis,ferroptosis,oxidative stress and androgen receptor(AR).Overall,this review aims to unveil the crosstalk between mitochondrial dysfunction and BPH and identify intrinsic mechanisms.展开更多
The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial d...The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas(hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.展开更多
Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynth...Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.展开更多
Alzheimer’s disease is a neurodegenerative disease that affected over 6.5 million people in the United States in 2021,with this number expected to double in the next 40 years without any sort of treatment.Due to its ...Alzheimer’s disease is a neurodegenerative disease that affected over 6.5 million people in the United States in 2021,with this number expected to double in the next 40 years without any sort of treatment.Due to its heterogeneity and complexity,the etiology of Alzheimer’s disease,especially sporadic Alzheimer’s disease,remains largely unclear.Compelling evidence suggests that brain glucose hypometabolism,preceding Alzheimer’s disease hallmarks,is involved in the pathogenesis of Alzheimer’s disease.Herein,we discuss the potential causes of reduced glucose uptake and the mechanisms underlying glucose hypometabolism and Alzheimer’s disease pathology.Specifically,decreased O-Glc NAcylation levels by glucose deficiency alter mitochondrial functions and together contribute to Alzheimer’s disease pathogenesis.One major problem with Alzheimer’s disease research is that the disease progresses for several years before the onset of any symptoms,suggesting the critical need for appropriate models to study the molecular changes in the early phase of Alzheimer’s disease progression.Therefore,this review also discusses current available sporadic Alzheimer’s disease models induced by metabolic abnormalities and provides novel directions for establishing a human neuronal sporadic Alzheimer’s disease model that better represents human sporadic Alzheimer’s disease as a metabolic disease.展开更多
Objective The inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rgl is reported to be neuroprotec...Objective The inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rgl is reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rgl can attenuate isoflurane-induced caspase activation via inhibiting mitochondrial dysfunction. Methods We investigated the effects of ginsenoside Rgl at concentrations of 12.5, 25, and 50 μmol/L and pretreatment times of 12 h and 24 h on isoflurane-induced caspase-3 activation in H4 naive and stably transfected H4 human neuroglioma cells that express full-length human amyloid precursor protein （APP） （H4-APP cells）. For mitochondrial dysfunction, we assessed mitochondrial permeability transition pore （mPTP） and adenosine-5＇-triphosphate （ATP） levels. We employed Western blot analysis, chemiluminescence, and flowcytometry. Results Here we show that pretreatment with 50 μmol/L ginsenoside Rgl for 12 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in H4-APP cells, while pretreatment with 25 and 50 μmol/L ginsenoside Rgl for 24 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in both H4 naive and H4-APP cells. Conclusion These data suggest that ginsenoside Rgl may ameliorate isoflurane-induced caspase-3 activation by inhibiting mitochondrial dysfunction. Pending further studies, these findings might recommend the use of ginsenoside Rgl in preventing and treating isoflurane-induced neurotoxicity.展开更多
The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct facto...The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct factors such as ischemia,hypoxia,excitotoxicity,and toxicity of free hemoglobin and its degradation products,which trigger mitochondrial dysfunction.Dysfunctional mitochondria release large amounts of reactive oxygen species,inflammatory mediators,and apoptotic proteins that activate apoptotic pathways,further damaging cells.In response to this array of damage,cells have adopted multiple mitochondrial quality control mechanisms through evolution,including mitochondrial protein quality control,mitochondrial dynamics,mitophagy,mitochondrial biogenesis,and intercellular mitochondrial transfer,to maintain mitochondrial homeostasis under pathological conditions.Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage.This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage,particularly mitochondrial quality control mechanisms.It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.展开更多
Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability,inhibit free radicals,and reduce cerebrospinal fluid p...Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability,inhibit free radicals,and reduce cerebrospinal fluid production.According to the latest guidelines for the treatment of traumatic brain injury in the United States,high-dose glucocorticoids cause neurological damage.To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect,rat controlled cortical impact models of traumatic brain injury were established.At 1 hour and 2 days after surgery,rat models were intraperitoneally administered dexamethasone 10 mg/kg.The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment.The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway.Western blot analysis and immunohistochemistry results showed that Ndufv2,Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group.These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits(Ndufs2 and Ndufv2),increase the expression of mitochondrial enzyme Maob,and upregulate synaptic-transmission-related protein Gria3.These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone.The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute(approval No.201802001)on June 6,2018.展开更多
Alzheimer＇s disease （AD） is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β （Aβ） deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, a...Alzheimer＇s disease （AD） is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β （Aβ） deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aβ precursor protein is cleaved to produce both extracellular and intracellular Aβ, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aβ neurotoxicity. In this review, we summarize the pathways ofAβ generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.展开更多
基金supported by the National Natural Science Foundation of China,No.82204663(to TZ)the Natural Science Foundation of Shandong Province,No.ZR2022QH058(to TZ).
文摘Modulations of mitochondrial dysfunction,which involve a series of dynamic processes such as mitochondrial biogenesis,mitochondrial fusion and fission,mitochondrial transport,mitochondrial autophagy,mitochondrial apoptosis,and oxidative stress,play an important role in the onset and progression of stroke.With a better understanding of the critical role of mitochondrial dysfunction modulations in post-stroke neurological injury,these modulations have emerged as a potential target for stroke prevention and treatment.Additionally,since effective treatments for stroke are extremely limited and natural products currently offer some outstanding advantages,we focused on the findings and mechanisms of action related to the use of natural products for targeting mitochondrial dysfunction in the treatment of stroke.Natural products achieve neuroprotective through multi-target regulation of mitochondrial dysfunction encompassing the following processes:(1)Mitochondrial biogenesis:Cordyceps and hydroxysafflor yellow A activate the peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor pathway,promote mitochondrial DNA replication and respiratory chain protein synthesis,and thereby restore energy supply in the ischemic penumbra.(2)Mitochondrial dynamics balance:Ginsenoside Rb3 promotes Opa1-mediated neural stem cell migration and diffusion for recovery of damaged brain tissue.(3)Mitochondrial autophagy:Gypenoside XVII selectively eliminates damaged mitochondria via the phosphatase and tensin homolog-induced kinase 1/Parkin pathway and blocks reactive oxygen species and the NOD-like receptor protein 3 inflammasome cascade,thereby alleviating blood-brain barrier damage.(4)Anti-apoptotic mechanisms:Ginkgolide K inhibits Bax mitochondrial translocation and downregulates caspase-3/9 activity,reducing neuronal programmed death induced by ischemia-reperfusion.(5)Oxidative stress regulation:Scutellarin exerts antioxidant properties and improves neurological function by modulating the extracellular signal-regulated kinase 5-Kruppel-like factor 2-endothelial nitric oxide synthase signaling pathway.(6)Intercellular mitochondrial transport:Neuroprotective effects of Chrysophanol are associated with accelerated mitochondrial transfer from astrocytes to neurons.Existing studies have confirmed that natural products exhibit neuroprotective effects through multidimensional interventions targeting mitochondrial dysfunction in both ischemic and hemorrhagic stroke models.However,their clinical translation still faces challenges,such as the difficulty in standardization due to component complexity,insufficient cross-regional clinical data,and the lack of long-term safety evaluations.Future research should aim to integrate new technologies,such as single-cell sequencing and organoid models,to deeply explore the mitochondria-targeting mechanisms of natural products and validate their efficacy through multicenter clinical trials,providing theoretical support and translational pathways for the development of novel anti-stroke drugs.
基金supported by grants from Collaborative Research Fund(Ref:C4032-21GF)General Research Grant(Ref:14114822)+1 种基金Group Research Scheme(Ref:3110146)Area of Excellence(Ref:Ao E/M-402/20)。
文摘Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.
文摘Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors,shaping the dynamic landscape of the developing brain.A major component of the developing brain that enables this dynamic is the white matter(WM),known to be affected in neurodevelopmental disorders(NDDs)(Rokach et al.,2024).WM formation is mediated by myelination,a multifactorial process driven by neuro-glia interactions dependent on proper neuronal functionality(Simons and Trajkovic,2006).Another key aspect of neurodevelopmental abnormalities involves neuronal dynamics and function,with recent advances significantly enhancing our understanding of both neuronal and glial mitochondrial function(Devine and Kittler,2018;Rojas-Charry et al.,2021).Energy homeostasis in neurons,attributed largely to mitochondrial function,is critical for proper functionality and interactions with oligodendrocytes(OLs),the cells forming myelin in the brain’s WM.We herein discuss the interplay between these processes and speculate on potential dysfunction in NDDs.
基金funded by Shanghai Yangpu District Science and Technology Commission(Grant No.YPQ202303(Xuejing Lin))Shanghai Yangpu Hospital Foundation(Grant No.Se1202420(Wenchao Wang)and Ye1202423(Juan Huang)).
文摘Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.
基金funding support from the hospital-level project of Taizhou People's Hospital(Project No.:ZL201944).
文摘Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression Omnibus(GEO)datasets showed that ZFP36 was a differentially expressed gene(DEG)in OS.Western blot and immunohistochemistry results showed that ZFP36 was downregulated in OS tumors and cell lines.ZFP36 overexpression plasmids and small interfering RNAs(siRNAs)were respectively transfected into OS cells.ZFP36 overexpression restrained proliferation,migration,and invasion in MG63 and U2OS cells,while ZFP36 knockdown displayed the opposite results.Moreover,ZFP36 overexpression increased the levels of intracellular Fe2t,reactive oxygen species(ROS),and malondialdehyde(MDA),and decreased the levels of glutathione(GSH),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11).ZFP36 overexpression disturbed mitochondrial membrane potential(MMP)and mitochondrial morphology in OS cells.However,ZFP36 knockdown had the opposite results.Mechanistic studies indicated that ZFP36 promoted E2F transcription factor 1(E2F1)messenger RNA(mRNA)degradation by binding to the AU-rich elements(AREs)within E2F130 untranslated region(30UTR)in OS cells.E2F1 overexpression abrogated the effects of ZFP36 overexpression on malignant progression,ferroptosis,and mitochondrial dysfunction in OS cells.Furthermore,E2F1 promoted the transcription activation of activating transcription factor 4(ATF4)by binding to ATF4 promoter.E2F1 knockdown inhibited malignant progression,and promoted ferroptosis and mitochondrial dysfunction in OS cells,which was abrogated by ATF4 overexpression.Additionally,MG63 cells transfected with lentivirus ZFP36 overexpression vector(Lv-ZFP36)were injected into nude mice and tumor growth was monitored.ZFP36 overexpression significantly suppressed OS tumor growth under in vivo settings.In conclusion,ZFP36 overexpression promoted ferroptosis and mitochondrial dysfunction and inhibited malignant progression in OS by regulating the E2F1/ATF4 axis.We may provide the promising ZFP36 target for OS treatment.
基金funded in part by Quanta Computer,Inc.,in Tanyuan,Taiwan,under contract number 6950759,as part of the AIR project.
文摘Deuterium is a heavy isotope of hydrogen,with an extra neutron,endowing it with unique biophysical and biochemical properties compared to hydrogen.The ATPase pumps in the mitochondria depend upon proton motive force to catalyze the reaction that produces ATP.Deuterons disrupt the pumps,inducing excessive reactive oxygen species and decreased ATP synthesis.The aim of this review is to develop a theory that mitochondrial dysfunction due to deuterium overload,systemically,is a primary cause of Parkinson’s disease(PD).The gut microbes supply deuterium-depleted short chain fatty acids(SCFAs)to the colonocytes,particularly butyrate,and an insufficient supply of butyrate may be a primary driver behind mitochondrial dysfunction in the gut,an early factor in PD.Indeed,low gut butyrate is a characteristic feature of PD.Mitochondrial dysfunction is a factor in many diseases,including all neurodegenerative diseases.Biological organisms have devised sophisticated strategies for protecting the ATPase pumps from deuterium overload.One such strategy may involve capturing deuterons in bis-allylic carbon atoms present in polyunsaturated fatty acids(PUFAs)in cardiolipin.Cardiolipin uniquely localizes to the inner membrane of the intermembrane space,tightly integrated into ATPase proteins.Bis-allylic carbon atoms can capture and retain deuterium,and,interestingly,deuterium doping in PUFAs can quench the chain reaction that causes massive damage upon lipid peroxidation.Neuronal cardiolipin is especially rich in docosahexaenoic acid(DHA),a PUFA with five bisallylic carbon atoms.Upon excessive oxidative stress,cardiolipin migrates to the outer membrane,where it interacts withα-synuclein(α-syn),the amyloidogenic protein that accumulates as fibrils in Lewy bodies in association with PD.Such interaction leads to pore formation and the launch of an apoptotic cascade.α-syn misfolding likely begins in the gut,and misfoldedα-syn travels along nerve fibers,particularly the vagus nerve,to reach the brainstem nuclei,where it can seed misfolding ofα-syn molecules already present there.Mitochondrial dysfunction in the gut may be a primary factor in PD,and low-deuterium nutrients may be therapeutic.
基金supported by the Science and Technology Program of Guangzhou(202206010140)the Guangdong Provincial Key Research and Development Program(2023B1111050003).
文摘Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis.The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA.As age advances,mitochondrial function declines progressively,which leads to an imbalance in chondrocyte energy homeostasis,partially initiating the process of cartilage degeneration.Elevated oxidative stress,impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology,with mitochondrial DNA haplogroups,particularly haplogroup J,influencing OA progression.Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases,with triphenylphosphonium(TPP)emerging as the most widely utilized molecule.Other strategies encompass Dequalinium(DQA),the Szeto-Schiller(SS)tetrapeptide family,the KLA peptide,and mitochondrial-penetrating peptides(MPP),etc.
基金financed by the Ryazan StateMedical University intra-university grant:Agreement No.1A/25 for the implementation of research on the topic:“Metabolic Markers of Impaired Adaptation to Hypoxia in COPD:The Role of Hyperhomocysteinemia and Carnitine Deficiency”dated 09 April 2025.
文摘Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and pulmonary vascular remodeling,rise with disease severity,and may contribute to the excess cardiovascular risk—although effect sizes and causality remain uncertain.This review centers on the homocysteine–carnitine relationship in COPD pathophysiology.Carnitine deficiency,prevalent in COPD,can worsen mitochondrial bioenergetics,promote accumulation of acyl intermediates,and reduce nitric oxide bioavailability via endothelial nitric oxide synthase uncoupling(eNOS).Conversely,restoring carnitine status in experimental and early clinical settings has been associated with lower homocysteine,improved nitric oxide signaling,and attenuation of vascular remodeling,suggesting a reciprocal link rather than a one-way pathway.We review existing evidence on various COPD phenotypes and severities,delineate mechanisms that connect homocysteine,carnitine metabolism,mitochondria,redox balance and eNOS uncoupling,and evaluate therapeutic strategies—ranging from lowering homocysteine with B-group vitamins to integrated approaches that also supportmitochondrial function and redox homeostasis,including targeted carnitine supplementation.The role of L-carnitine as a potential therapeutic agent for lowering homocysteine and improving mitochondrial and vascular function warrants further investigation,as it may help slow the progression of COPD and its related comorbidities.
文摘Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in reduced ATP synthesis,elevated reactive oxygen species(ROS)formation,and mitochondrial malfunction,which instigates oxidative stress and cellular damage,critical elements in neurodegenerative disorders like Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Alzheimer’s disease(AD).In addition to causing direct neuronal injury,rotenone significantly contributes to the activation of glial cells,specifically microglia and astrocytes.Activated microglia assumes a proinflammatory(M1)phenotype,distinguished by the secretion of inflammatory cytokines including tumor necrosis factor alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),with the generation of nitric oxide and ROS,which exacerbate the neuronal injury.Astrocytes can intensify neuroinflammation by secreting proinflammatory molecules and impairing their neuroprotective roles.Our hypothesis is that rotenone is posited to elicit a neuroinflammatory response via mitochondrial malfunction,ROS generation,and the activation of proinflammatory pathways in microglia and astrocytes.This mechanism leads to accelerated neuronal impair-ment,promoting neurodegeneration.Comprehending the inflammatory pathways activated by rotenone is crucial for pinpointing therapeutic targets to regulate glial responses and mitigate the advancement of neurodegenerative disorders linked to mitochondrial malfunction and chronic inflammation.This review examines the function of glial cells and critical inflammatory pathways,namely Nuclear factor kappaβ(NF-κB),Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin(PI3K/AKT/mTOR),and Wnt/β-catenin signaling pathway in Parkinson’s disease,Alzheimer’s disease,and ALS,emphasizing illness-specific responses and the translational constraints of rotenone-based models.The objective is to consolidate existing understanding regarding the role of rotenone-induced mitochondrial failure in promoting glial activation and neuroinflammation,highlighting the necessity for additional research into these pathways.Despite the prevalent application of rotenone in experimental models,its specific effects on glial-mediated inflammation are inadequately comprehended,necessitating further investigation to guide the formulation of targeted therapeutic strategies.
基金Supported by National Natural Science Foundation of China,No.8217030254.
文摘Acute pancreatitis(AP)is a life-threatening inflammatory condition triggered by the premature activation of trypsin.The limited understanding of its underlying pathophysiology remains a key obstacle to the development of targeted therapies.Mounting evidence now underscores mitochondrial dysfunction as a critical pathogenic driver in AP.Cellular mitochondrial dysfunction often precedes both cytokine release and trypsin activation,potentially serving as a primary initiator in the development and advancement of AP.Mitochondrial dysfunction is associated with calcium overload,inflammatory reactions,mitochondrial permeability transition pore opening,mitophagy damage,and other potential pathogenesis of pancreatic cell injury.Elucidating the impact of mitochondrial injury in AP may facilitate the development of innovative treatment approaches.This review provides a comprehensive and systematic analysis of the pivotal role of mitochondria in regulating pancreatic homeostasis,while evaluating emerging therapeutic strategies aimed at mitigating mitochondrial dysfunction.By integrating cuttingedge research findings,this work highlights the translational potential of these advancements in redefining diagnostic frameworks and optimizing therapeutic approaches for the management of AP.
文摘Background:Acute Myeloid Leukemia(AML)is a highly aggressive clonal hematological malignancy with limited treatment options.This study aimed to evaluate the therapeutic potential of nigericin,a polyether ionophore derived from Streptomyces DASNCL-29,as a mitochondrial-targeted agent for AML treatment.Methods:Nigericin was isolated from Streptomyces DASNCL-29 and characterized via chromatography and NMR.Its cytotoxicity was tested in MOLM13(sensitive and venetoclax-resistant)and HL60(sensitive and cytarabine-resistant)cells using the MTT assay.Mitochondrial dysfunction was assessed by measuring reactive oxygen species(ROS),mitochondrial membrane potential(Δψm),and mitochondrial mass.Apoptosis was evaluated with Annexin V/PI assays and immunoblotting,while proteomic analysis was conducted using Liquid Chromatography-Tandem Mass Spectrometry(LC-MS/MS)to identify differentially regulated proteins.Results:Nigericin demonstrated potent cytotoxicity with IC50 values of 57.02 nM in MOLM13-sensitive,35.29 nM in MOLM13-resistant,20.49 nM in HL60-sensitive,and 1.197 nM in HL60-cytarabine-resistant cells.Apoptosis was confirmed by Annexin V/PI staining and caspase-3/PARP cleavage,along with MCL-1 downregulation.Mitochondrial dysfunction was evident from increased ROS,reducedΔψm,and decreased mitochondrial mass.Proteomic profiling identified 264 dysregulated proteins,including a 3.8-fold upregulation of Succinate Dehydrogenase[Ubiquinone]Flavoprotein Subunit A(SDHA).Conclusion:Nigericin induces apoptosis in AML cells by disrupting mitochondrial function and enhancing oxidative stress.Its nanomolar potency highlights the need for further mechanistic studies and in vivo evaluations to explore its potential in AML treatment.
基金supported by the National Key Research and Development Program(2022YFD1600402)Hebei Provincial Major Science and Technology Achievement Transformation Project(21287101Z)Hebei Provincial Innovation and Entrepreneurship Team Project(215A7102D)。
文摘Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiable matter(USM),a composition of highly active ingredients found in walnut oil,has demonstrated antioxidant effects.This study aims to explore the neuroprotective effects of USM on d-galactose-treated C57BL/6 mice and elucidate its underlying mechanism,which was validated in PC12 cells treated with d-galactose.The results of behavioral tests demonstrated that USM significantly improved cognitive deficits associated with aging.The morphological analysis demonstrated that USM effectively alleviated hippocampal neuronal damage,synaptic impairment,and mitochondrial dysfunction induced by d-galactose.Furthermore,USM significantly increases the antioxidant enzymes activity while reducing the malondialdehyde and reactive oxygen species levels.The results suggest that USM can mitigate age-related symptoms caused by d-galactose by activating the nuclear factor erythroid-2-related factor 2 signaling pathway,which enhances the expression of antioxidant enzymes,restore redox balance,and improves synaptic and mitochondrial functions.This has a positive on improving cognition and memory disorders in elderly mice.
文摘Benign prostatic hyperplasia(BPH)represents a prevalent etiology of lower urinary tract symptoms(LUTS)in the male population,clinically defined by a nonmalignant proliferation of prostatic tissue.While BPH exhibits a high prevalence among older male populations globally,the precise underlying mechanisms contributing to its development remain incompletely elucidated.Mitochondria,essential organelles within eukaryotic cells,are critical for cellular bioenergetics,the regulation of reactive oxygen species(ROS)generation,and the modulation of cell death pathways.The maintenance of mitochondrial homeostasis involves a complex interplay of processes.By synthesizing previous literature,this review discusses mitochondrial homeostasis in prostate glands and the role of mitochondrial dysfunction in the context of BPH.Furthermore,the review delved into each dimension of mitochondrial dysfunction in the specific etiology of BPH,highlighting its impact on cell survival,apoptosis,ferroptosis,oxidative stress and androgen receptor(AR).Overall,this review aims to unveil the crosstalk between mitochondrial dysfunction and BPH and identify intrinsic mechanisms.
基金supported by Fondecyt 1200908(to JF)the Conicyt 21141247(to JDP)。
文摘The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas(hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.
文摘Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.
基金supported by the Georgia Research Alliance and the University of Georgia(to GWH)。
文摘Alzheimer’s disease is a neurodegenerative disease that affected over 6.5 million people in the United States in 2021,with this number expected to double in the next 40 years without any sort of treatment.Due to its heterogeneity and complexity,the etiology of Alzheimer’s disease,especially sporadic Alzheimer’s disease,remains largely unclear.Compelling evidence suggests that brain glucose hypometabolism,preceding Alzheimer’s disease hallmarks,is involved in the pathogenesis of Alzheimer’s disease.Herein,we discuss the potential causes of reduced glucose uptake and the mechanisms underlying glucose hypometabolism and Alzheimer’s disease pathology.Specifically,decreased O-Glc NAcylation levels by glucose deficiency alter mitochondrial functions and together contribute to Alzheimer’s disease pathogenesis.One major problem with Alzheimer’s disease research is that the disease progresses for several years before the onset of any symptoms,suggesting the critical need for appropriate models to study the molecular changes in the early phase of Alzheimer’s disease progression.Therefore,this review also discusses current available sporadic Alzheimer’s disease models induced by metabolic abnormalities and provides novel directions for establishing a human neuronal sporadic Alzheimer’s disease model that better represents human sporadic Alzheimer’s disease as a metabolic disease.
基金supported by 2013 Beijing NOVA Program(Z131107000413044)
文摘Objective The inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rgl is reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rgl can attenuate isoflurane-induced caspase activation via inhibiting mitochondrial dysfunction. Methods We investigated the effects of ginsenoside Rgl at concentrations of 12.5, 25, and 50 μmol/L and pretreatment times of 12 h and 24 h on isoflurane-induced caspase-3 activation in H4 naive and stably transfected H4 human neuroglioma cells that express full-length human amyloid precursor protein （APP） （H4-APP cells）. For mitochondrial dysfunction, we assessed mitochondrial permeability transition pore （mPTP） and adenosine-5＇-triphosphate （ATP） levels. We employed Western blot analysis, chemiluminescence, and flowcytometry. Results Here we show that pretreatment with 50 μmol/L ginsenoside Rgl for 12 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in H4-APP cells, while pretreatment with 25 and 50 μmol/L ginsenoside Rgl for 24 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in both H4 naive and H4-APP cells. Conclusion These data suggest that ginsenoside Rgl may ameliorate isoflurane-induced caspase-3 activation by inhibiting mitochondrial dysfunction. Pending further studies, these findings might recommend the use of ginsenoside Rgl in preventing and treating isoflurane-induced neurotoxicity.
基金supported by the National Natural Science Foundation of China,Nos.82130037(to CH),81971122(to CH),82171323(to WL)the Natural Science Foundation of Jiangsu Province of China,No.BK20201113(to WL)。
文摘The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct factors such as ischemia,hypoxia,excitotoxicity,and toxicity of free hemoglobin and its degradation products,which trigger mitochondrial dysfunction.Dysfunctional mitochondria release large amounts of reactive oxygen species,inflammatory mediators,and apoptotic proteins that activate apoptotic pathways,further damaging cells.In response to this array of damage,cells have adopted multiple mitochondrial quality control mechanisms through evolution,including mitochondrial protein quality control,mitochondrial dynamics,mitophagy,mitochondrial biogenesis,and intercellular mitochondrial transfer,to maintain mitochondrial homeostasis under pathological conditions.Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage.This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage,particularly mitochondrial quality control mechanisms.It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.
基金This study was supported by the National Natural Science Foundation of China,No.81771327(to BYL)the Platform Construction of Basic Research and Clinical Translation of Nervous System Injury,China,No.PXM2020_026280_000002(to BYL)the Scientific Research and Cultivation Fund of the Beijing Neurosurgical Institute,China,No.2020002(to FN).
文摘Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability,inhibit free radicals,and reduce cerebrospinal fluid production.According to the latest guidelines for the treatment of traumatic brain injury in the United States,high-dose glucocorticoids cause neurological damage.To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect,rat controlled cortical impact models of traumatic brain injury were established.At 1 hour and 2 days after surgery,rat models were intraperitoneally administered dexamethasone 10 mg/kg.The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment.The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway.Western blot analysis and immunohistochemistry results showed that Ndufv2,Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group.These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits(Ndufs2 and Ndufv2),increase the expression of mitochondrial enzyme Maob,and upregulate synaptic-transmission-related protein Gria3.These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone.The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute(approval No.201802001)on June 6,2018.
基金supported by the National Natural Science Foundation of China(31071512)the Subsidy for Outstanding People of Beijing Municipality, China (2012D005022000006)the Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality, China [PHR(IHLB), PHR20090514]
文摘Alzheimer＇s disease （AD） is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β （Aβ） deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aβ precursor protein is cleaved to produce both extracellular and intracellular Aβ, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aβ neurotoxicity. In this review, we summarize the pathways ofAβ generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.
