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
Mitochondria are central regulators of cellular energy metabolism,redox balance,and survival,and their dysfunction contributes to neurodegenerative,cardiovascular,and metabolic diseases,as well as aging.Beyond its rol...Mitochondria are central regulators of cellular energy metabolism,redox balance,and survival,and their dysfunction contributes to neurodegenerative,cardiovascular,and metabolic diseases,as well as aging.Beyond its role as a circadian hormone,melatonin is now recognized as a key modulator of mitochondrial physiology.This review provides an overview of the mechanisms by which melatonin can preserve mitochondrial function through multifaceted mechanisms.Experimental evidence shows that melatonin enhances the activity of electron transport chain(ETC)complexes,stabilizes the mitochondrial membrane potential(Δψ),and prevents cardiolipin(CL)peroxidation,thereby limiting permeability transition pore(mPTP)opening and cytochrome c release.Through its direct radical scavenging capacity and the upregulation of mitochondrial antioxidant defenses,melatonin protects against oxidative stress(OS)and preserves mitochondrial DNA integrity.Melatonin also regulates mitochondrial dynamics by promoting fusion,restraining excessive fission,and supporting quality control mechanisms such as mitophagy,unfolded protein response(UPR),and proteostasis.Moreover,melatonin influences mitochondrial biogenesis and intercellular communication through tunneling nanotubes(TNTs)and mitokine signaling.Thus,melatonin may represent a promising multifaceted therapeutic strategy for preserving mitochondrial homeostasis in a range of pathological conditions,including neurodegeneration and cardiovascular and metabolic diseases.However,a significant translational gap still remains between the promising preclinical data and the established clinical practice.Therefore,the aim of this review is to provide a comprehensive synthesis of current knowledge on the mechanisms through which melatonin modulates mitochondrial function and to discuss its potential therapeutic implications in neurodegenerative,cardiovascular,and metabolic diseases.展开更多
Aging is characterized by a progressive decline in physiological function,driven by intrinsic mechanisms(primary aging)and modifiable factors(secondary aging),ultimately leading to multimorbidity,disability,and mortal...Aging is characterized by a progressive decline in physiological function,driven by intrinsic mechanisms(primary aging)and modifiable factors(secondary aging),ultimately leading to multimorbidity,disability,and mortality.Mitochondrial dysfunction,a major hallmark of aging,plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia.With age,mitochondrial quality control processes,including biogenesis,mitophagy,and dynamics,become dysregulated,impairing energy metabolism and muscle homeostasis.Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty,such as the decrease in walking speed and muscle strength,making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity.Mitohormetic agents induce reversible mitochondrial stress,triggering adaptive responses that enhance function.Among these interventions,physical exercise,particularly endurance and resistance training(RT),has been reported to be among the most effective,as it may modulate mitochondrial biogenesis,dynamics,and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α)and mitochondrial transcription factor A(TFAM)expression,mitochondrial deoxyribonucleic acid(mtDNA)copy number,and mitochondrial content.Chronic RT can also elevate fusion and fission markers,potentially as a compensatory mechanism to mitigate mitochondrial damage.Apart from exercise,mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field.By modulating mitochondrial bioenergetics and dynamics,they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.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
Aging,mitochondria,and neurodegenerative diseases:Aging is often viewed as the buildup of changes that lead to the gradual transformations associated with getting older,along with a rising likelihood of disease and mo...Aging,mitochondria,and neurodegenerative diseases:Aging is often viewed as the buildup of changes that lead to the gradual transformations associated with getting older,along with a rising likelihood of disease and mortality.Although organis m-wide deterioration is observed during aging,organs with high metabolic demand,such as the brain,are more vulnerable.展开更多
Delayed neurocognitive recovery following anesthesia and surgery is a common complication in older adult patients.Synapses are fundamental to cognitive function.The activity of synapses heavily depends on the energy s...Delayed neurocognitive recovery following anesthesia and surgery is a common complication in older adult patients.Synapses are fundamental to cognitive function.The activity of synapses heavily depends on the energy supplied by synaptic mitochondria,which are significantly influenced by oxidative stress.Sirtuin 3 is a histone deacetylase located in the mitochondrial matrix that plays a pivotal role in regulating mitochondrial function.However,it remains unclear whether and how sirtuin 3 is involved in the development of delayed cognitive recovery.Therefore,in this study,we investigated the potential role of sirtuin 3 in synapses during delayed neurocognitive recovery.Our results showed that anesthesia and surgery induced cognitive impairment in mice and reduced sirtuin 3 protein expression.Overexpression of sirtuin 3 inhibited opening of the mitochondrial permeability transition pore by reducing acetylation of K166 on cyclophilin D and also rescued cognitive impairment.Aged mice carrying the cyclophilin D-K166R mutation exhibited significantly reduced cognitive impairment.Similarly,administering the mitochondrial permeability transition pore blocker,cyclosporine A,effectively alleviated the decline in synaptic mitochondrial function and cognitive impairment caused by anesthesia and surgery in aged mice.These results indicate that the sirtuin 3/cyclophilin D-K166/mPTP signaling pathway in hippocampal synaptic mitochondria is involved in delayed neurocognitive recovery of aged mice,suggesting this pathway could serve as a potential target for treatment.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
Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Alt...Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.展开更多
Skeletal muscle health and function are essential determinants of metabolic health,physical performance,and overall quality of life.The quality of skeletal muscle is heavily dependent on the complex mitochondrial reti...Skeletal muscle health and function are essential determinants of metabolic health,physical performance,and overall quality of life.The quality of skeletal muscle is heavily dependent on the complex mitochondrial reticulum that contributes toward its unique adaptability.It is now recognized that mitochondrial perturbations can activate various innate immune pathways,such as the nucleotide-binding oligomerization domain(NOD)-like receptor protein 3(NLRP3)inflammasome complex by propagating inflammatory signaling in response to damage-associated molecular patterns(DAMPs).The NLRP3 inflammasome is a multimeric protein complex and is a prominent regulator of innate immunity and cell death by mediating the activation of caspase-1,pro-inflammatory cytokines interleukin-1βand interleukin-18 and pro-pyroptotic protein gasdermin-D.While several studies have begun to demonstrate the relationship between various mitochondrial DAMPs(mtDAMPs)and NLRP3 inflammasome activation,the influence of various metabolic states on the production of these DAMPs and subsequent inflammatory profile remains poorly understood.This narrative review aimed to address this by highlighting the effects of skeletal muscle use and disuse on mitochondrial quality mechanisms including mitochondrial biogenesis,fusion,fission and mitophagy.Secondly,this review summarized the impact of alterations in mitochondrial quality control mechanisms following muscle denervation,aging,and exercise training in relation to NLRP3 inflammasome activation.By consolidating the current body of literature,this work aimed to further the understanding of innate immune signaling within skeletal muscle,which can highlight areas for future research and therapeutic strategies to regulate NLRP3 inflammasome activation during divergent metabolic conditions.展开更多
Objective:Hepatocellular carcinoma(HCC)ranks among themost prevalentmalignant tumors globally.Metabolically associated fatty liver disease is a significant risk factor for HCC.Adiponectin,a key regulatory protein in g...Objective:Hepatocellular carcinoma(HCC)ranks among themost prevalentmalignant tumors globally.Metabolically associated fatty liver disease is a significant risk factor for HCC.Adiponectin,a key regulatory protein in glucolipid metabolism,presents potential as an anti-tumor target in HCC cells.The study focused on evaluating the anti-HCC properties of AdipoRon,an agonist of the adiponectin receptor.Method:Cell viability and proliferation were assessed using the cell counting kit-8 and colony formation assays,respectively.AdipoRon’s effect on HCC cell damage was evaluated via flow cytometry,apoptosis,and(lactate dehydrogenase)LDH assays.Mitochondrial function was evaluated by measuring mitochondrial membrane potential(MMP),ATP levels,and Complex I activity.Additionally,mitochondrial reactive oxygen species(ROS)and calcium(Ca^(2+))levelswere analyzed usingMitoSOXRed and Rhod-2 AM probes,respectively.Results:Our findings indicated that AdipoRon suppressed the proliferation of HCC cells and triggered apoptosis,with both effects being dose-dependent.Furthermore,AdipoRon caused a decrease in mitochondrial membrane potential,ATP levels,and Complex I activity,alongside the generation of mitochondrial ROS.Notably,AdipoRon disrupted intracellular Ca^(2+)homeostasis by causing mitochondrial Ca^(2+)overload due to release fromthe endoplasmic reticulum(ER).Additionally,AdipoRon promoted Ca^(2+)release from the ER by activating the PLC-IP3-IP3R pathway.The resulting mitochondrial Ca^(2+)overload enhances the anti-HCC effect when combined with chemotherapeutic drugs.Conclusions:Therefore,our study demonstrates thatAdipoRon promotesmitochondrial Ca^(2+)overload and apoptosis in HCC cells by activating the PLC-IP3-IP3R signaling pathway.AdipoRon has the potential to become an effective anti-HCC drug.展开更多
The Fujian oyster(Crassostrea angulata) is an economically significant shellfish species distributed mainly along the Fujian coast, Southeast China. However, its genetic diversity and structure remain unclear. The mai...The Fujian oyster(Crassostrea angulata) is an economically significant shellfish species distributed mainly along the Fujian coast, Southeast China. However, its genetic diversity and structure remain unclear. The main distribution area of the C. angulata is located in Fujian, South China. In total, 420 C. angulata were collected from 14 natural habitats(populations) along the Fujian coast, and their genetic diversity and structure were analyzed in the mitochondrial COI and nuclear gene ITS2 sequences. Results reveal that all the 14 populations of C. angulata exhibited high levels of genetic diversity, with a total of 57(haplotype diversity: 0.811±0.016) and 124(haplotype diversity: 0.912±0.007) haplotypes revealed by COI and ITS2, respectively. Notably, significant intermediate level of genetic differentiations between the Ningde Zhujiang(ZJ) population(FS T by COI: 0.035–0.142, P<0.05;FS T by ITS2: 0.078–0.123, P<0.05) with other populations were observed for the first time, which is also supported by the results of molecular variance analysis(FC T by COI: 0.105, P<0.05;FC T by ITS2: 0.086, P<0.05) and the clustering of the ZJ population into distinct branches in the interpopulation genetic differentiation tree. Furthermore, the evolutionary tree and haplotype network analyses do not support the formation of a clear geographical genealogical structure among these 14 populations. In addition, the population dynamics analysis suggests that the C. angulata may have undergone expansion during the third ice age of the Pleistocene. These results provide a reference for the preservation and further genetic improvement of C. angulata.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
Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis(OA).However,the underlying mechanisms governing mitochondrial self...Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis(OA).However,the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive.In this study,we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes.Genetically overexpressing PTEN-induced putative kinase 1(PINK1)protects against cartilage degeneration by removing defective mitochondria.PINK1 knockout aggravated cartilage damage due to impaired mitophagy.SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism.Specifically,PINK1 phosphorylated PKM2 at the Ser127 site,preserving its active tetrameric form.This inhibited nuclear translocation and the interaction withβ-catenin,resulting in a metabolic shift and increased energy production.Finally,a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions.Overall,this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.展开更多
Mitochondria are double-membrane organelles within the cytoplasm,primarily responsible for the efficient production of ATP through oxidative phosphorylation(OXPHOS).These organelles harbor an autonomous genetic system...Mitochondria are double-membrane organelles within the cytoplasm,primarily responsible for the efficient production of ATP through oxidative phosphorylation(OXPHOS).These organelles harbor an autonomous genetic system independent of the nuclear genome,encoded by mitochondrial DNA(mtDNA).Human mitochondria contain a compact 16.6-kilobase circular genome(37 genes,13 protein-coding)that relies on over 1000 nuclear-encoded proteins for its functionality.The mtDNA forms a double-stranded structure where both the sense and antisense strands are transcribed into polycistronic precursors.The heavy(H)strand encodes 12 mRNAs,2 rRNAs,and 14 tRNAs,whereas the light(L)strand produces 1 mRNA and 8 tRNAs.These primary transcripts undergo extensive processing and maturation,including cleavage,RNA modifications,and polyadenylation,yielding functional tRNAs,rRNAs,and mRNAs.Characteristically,most mRNAs and rRNAs are interspersed with tRNA genes,which serve as recognition sites for endonucleases that process the primary transcripts into individual RNA units through site-specific cleavage at tRNA boundaries.展开更多
Mitochondria are fundamental organelles that play a crucial role in cellular energy metabolism,substance metabolism,and various essential cellular signaling pathways.The dysfunction of mitochondria is significantly im...Mitochondria are fundamental organelles that play a crucial role in cellular energy metabolism,substance metabolism,and various essential cellular signaling pathways.The dysfunction of mitochondria is significantly implicated in the onset and progression of aging,neurodegenerative diseases,metabolic disorders,and tumors,thereby rendering mitochondria-targeted regulation,a vital strategy for disease prevention and treatment.The recently developed mitochondrial membrane chromatography(MMC)technique,which immobilizes mitochondrial proteins as a chromatographic separation medium,has shown great potential for efficiently screening mitochondria-targeted modulators from complex compound library.In contrast to traditional screening methods,MMC has no need to purify mitochondrial proteins and can preserve its in situ and physiological conformation.Consequently,it presents broader application prospects for screening mitochondrial modulators as well as investigating receptor-ligand interactions involving any target protein associated with mitochondria.This review aims to elucidate the critical role of mitochondria in the development and progression of major chronic diseases,discuss recent advancements and applications of MMC,and propose future directions for MMC in the identification of novel mitochondrial modulators.展开更多
In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release f...In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.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
Mitochondria play an essential role in neural function,such as supporting normal energy metabolism,regulating reactive oxygen species,buffering physiological calcium loads,and maintaining the balance of morphology,sub...Mitochondria play an essential role in neural function,such as supporting normal energy metabolism,regulating reactive oxygen species,buffering physiological calcium loads,and maintaining the balance of morphology,subcellular distribution,and overall health through mitochondrial dynamics.Given the recent technological advances in the assessment of mitochondrial structure and functions,mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,mild cognitive impairment,and postoperative cognitive dysfunction.This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences,from the perspectives of energy metabolism,oxidative stress,calcium homeostasis,and mitochondrial dynamics(including fission-fusion,transport,and mitophagy).展开更多
The retina,a crucial neural tissue,is responsible for transforming light signals into visual information,a process that necessitates a significant amount of energy.Mitochondria,the primary powerhouses of the cell,play...The retina,a crucial neural tissue,is responsible for transforming light signals into visual information,a process that necessitates a significant amount of energy.Mitochondria,the primary powerhouses of the cell,play an integral role in retinal physiology by fulfilling the high-energy requirements of photoreceptors and secondary neurons through oxidative phosphorylation.In a healthy state,mitochondria ensure proper visual function by facilitating efficient conversion and transduction of visual signals.However,in retinal degenerative diseases,mitochondrial dysfunction significantly contributes to disease progression,involving a decline in membrane potential,the occurrence of DNA mutations,increased oxidative stress,and imbalances in quality-control mechanisms.These abnormalities lead to an inadequate energy supply,the exacerbation of oxidative damage,and the activation of cell death pathways,ultimately resulting in neuronal injury and dysfunction in the retina.Mitochondrial transplantation has emerged as a promising strategy for addressing these challenges.This procedure aims to restore metabolic activity and function in compromised cells through the introduction of healthy mitochondria,thereby enhancing the cellular energy production capacity and offering new strategies for the treatment of retinal degenerative diseases.Although mitochondrial transplantation presents operational and safety challenges that require further investigation,it has demonstrated potential for reviving the vitality of retinal neurons.This review offers a comprehensive examination of the principles and techniques underlying mitochondrial transplantation and its prospects for application in retinal degenerative diseases,while also delving into the associated technical and safety challenges,thereby providing references and insights for future research and treatment.展开更多
The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findin...The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.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.
文摘Mitochondria are central regulators of cellular energy metabolism,redox balance,and survival,and their dysfunction contributes to neurodegenerative,cardiovascular,and metabolic diseases,as well as aging.Beyond its role as a circadian hormone,melatonin is now recognized as a key modulator of mitochondrial physiology.This review provides an overview of the mechanisms by which melatonin can preserve mitochondrial function through multifaceted mechanisms.Experimental evidence shows that melatonin enhances the activity of electron transport chain(ETC)complexes,stabilizes the mitochondrial membrane potential(Δψ),and prevents cardiolipin(CL)peroxidation,thereby limiting permeability transition pore(mPTP)opening and cytochrome c release.Through its direct radical scavenging capacity and the upregulation of mitochondrial antioxidant defenses,melatonin protects against oxidative stress(OS)and preserves mitochondrial DNA integrity.Melatonin also regulates mitochondrial dynamics by promoting fusion,restraining excessive fission,and supporting quality control mechanisms such as mitophagy,unfolded protein response(UPR),and proteostasis.Moreover,melatonin influences mitochondrial biogenesis and intercellular communication through tunneling nanotubes(TNTs)and mitokine signaling.Thus,melatonin may represent a promising multifaceted therapeutic strategy for preserving mitochondrial homeostasis in a range of pathological conditions,including neurodegeneration and cardiovascular and metabolic diseases.However,a significant translational gap still remains between the promising preclinical data and the established clinical practice.Therefore,the aim of this review is to provide a comprehensive synthesis of current knowledge on the mechanisms through which melatonin modulates mitochondrial function and to discuss its potential therapeutic implications in neurodegenerative,cardiovascular,and metabolic diseases.
基金Instituto de Salud CarlosⅢCB16/10/00435(CIBERFES)(PID2022-142470OB-I00)from the Spanish Ministry of Innovation and Science+3 种基金PROMETEO(CIPROM/2022/56)de"Consellería de Educación,Universidades,y Empleo de la Generalitat Valenciana"EU Funded H2020-DIABFRAIL-LATAM(Ref:825546)Red EXERNET-RED DE EJERCICIO FISICO Y SALUD(RED2022-134800-T)Agencia Estatal de Investigacion(Ministerio de Ciencias e Innovación)funded by Generalitat Valenciana and co-financed with FEDER funds(OP FEDER of Comunitat Valenciana 2014–2020).A.G-G(FPU22/02539)and S.S-R(PREP2022-000563)received a predoctoral grant financed by the Spanish Ministry of Universities.
文摘Aging is characterized by a progressive decline in physiological function,driven by intrinsic mechanisms(primary aging)and modifiable factors(secondary aging),ultimately leading to multimorbidity,disability,and mortality.Mitochondrial dysfunction,a major hallmark of aging,plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia.With age,mitochondrial quality control processes,including biogenesis,mitophagy,and dynamics,become dysregulated,impairing energy metabolism and muscle homeostasis.Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty,such as the decrease in walking speed and muscle strength,making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity.Mitohormetic agents induce reversible mitochondrial stress,triggering adaptive responses that enhance function.Among these interventions,physical exercise,particularly endurance and resistance training(RT),has been reported to be among the most effective,as it may modulate mitochondrial biogenesis,dynamics,and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α)and mitochondrial transcription factor A(TFAM)expression,mitochondrial deoxyribonucleic acid(mtDNA)copy number,and mitochondrial content.Chronic RT can also elevate fusion and fission markers,potentially as a compensatory mechanism to mitigate mitochondrial damage.Apart from exercise,mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field.By modulating mitochondrial bioenergetics and dynamics,they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.
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Aging,mitochondria,and neurodegenerative diseases:Aging is often viewed as the buildup of changes that lead to the gradual transformations associated with getting older,along with a rising likelihood of disease and mortality.Although organis m-wide deterioration is observed during aging,organs with high metabolic demand,such as the brain,are more vulnerable.
基金supported by the National Natural Science Foundation of China,Nos.81701040(to HM),82071180(to HM),82271206(to TL),82171191(to YW),82371211(to YW)the Natural Science Foundation of Beijing,No.7212023(to HM)Key Subject of the Natural Science Foundation ofJiangsu Province for Colleges and Universities,No.23KJA320009(to YW).
文摘Delayed neurocognitive recovery following anesthesia and surgery is a common complication in older adult patients.Synapses are fundamental to cognitive function.The activity of synapses heavily depends on the energy supplied by synaptic mitochondria,which are significantly influenced by oxidative stress.Sirtuin 3 is a histone deacetylase located in the mitochondrial matrix that plays a pivotal role in regulating mitochondrial function.However,it remains unclear whether and how sirtuin 3 is involved in the development of delayed cognitive recovery.Therefore,in this study,we investigated the potential role of sirtuin 3 in synapses during delayed neurocognitive recovery.Our results showed that anesthesia and surgery induced cognitive impairment in mice and reduced sirtuin 3 protein expression.Overexpression of sirtuin 3 inhibited opening of the mitochondrial permeability transition pore by reducing acetylation of K166 on cyclophilin D and also rescued cognitive impairment.Aged mice carrying the cyclophilin D-K166R mutation exhibited significantly reduced cognitive impairment.Similarly,administering the mitochondrial permeability transition pore blocker,cyclosporine A,effectively alleviated the decline in synaptic mitochondrial function and cognitive impairment caused by anesthesia and surgery in aged mice.These results indicate that the sirtuin 3/cyclophilin D-K166/mPTP signaling pathway in hippocampal synaptic mitochondria is involved in delayed neurocognitive recovery of aged mice,suggesting this pathway could serve as a potential target for treatment.
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.
文摘Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.
文摘Skeletal muscle health and function are essential determinants of metabolic health,physical performance,and overall quality of life.The quality of skeletal muscle is heavily dependent on the complex mitochondrial reticulum that contributes toward its unique adaptability.It is now recognized that mitochondrial perturbations can activate various innate immune pathways,such as the nucleotide-binding oligomerization domain(NOD)-like receptor protein 3(NLRP3)inflammasome complex by propagating inflammatory signaling in response to damage-associated molecular patterns(DAMPs).The NLRP3 inflammasome is a multimeric protein complex and is a prominent regulator of innate immunity and cell death by mediating the activation of caspase-1,pro-inflammatory cytokines interleukin-1βand interleukin-18 and pro-pyroptotic protein gasdermin-D.While several studies have begun to demonstrate the relationship between various mitochondrial DAMPs(mtDAMPs)and NLRP3 inflammasome activation,the influence of various metabolic states on the production of these DAMPs and subsequent inflammatory profile remains poorly understood.This narrative review aimed to address this by highlighting the effects of skeletal muscle use and disuse on mitochondrial quality mechanisms including mitochondrial biogenesis,fusion,fission and mitophagy.Secondly,this review summarized the impact of alterations in mitochondrial quality control mechanisms following muscle denervation,aging,and exercise training in relation to NLRP3 inflammasome activation.By consolidating the current body of literature,this work aimed to further the understanding of innate immune signaling within skeletal muscle,which can highlight areas for future research and therapeutic strategies to regulate NLRP3 inflammasome activation during divergent metabolic conditions.
基金supported by the Research Fund of Anhui Institute of Translational Medicine(2023zhyx-C84)Natural Science Research Project of Anhui Higher Education Institutions(2024AH050804).
文摘Objective:Hepatocellular carcinoma(HCC)ranks among themost prevalentmalignant tumors globally.Metabolically associated fatty liver disease is a significant risk factor for HCC.Adiponectin,a key regulatory protein in glucolipid metabolism,presents potential as an anti-tumor target in HCC cells.The study focused on evaluating the anti-HCC properties of AdipoRon,an agonist of the adiponectin receptor.Method:Cell viability and proliferation were assessed using the cell counting kit-8 and colony formation assays,respectively.AdipoRon’s effect on HCC cell damage was evaluated via flow cytometry,apoptosis,and(lactate dehydrogenase)LDH assays.Mitochondrial function was evaluated by measuring mitochondrial membrane potential(MMP),ATP levels,and Complex I activity.Additionally,mitochondrial reactive oxygen species(ROS)and calcium(Ca^(2+))levelswere analyzed usingMitoSOXRed and Rhod-2 AM probes,respectively.Results:Our findings indicated that AdipoRon suppressed the proliferation of HCC cells and triggered apoptosis,with both effects being dose-dependent.Furthermore,AdipoRon caused a decrease in mitochondrial membrane potential,ATP levels,and Complex I activity,alongside the generation of mitochondrial ROS.Notably,AdipoRon disrupted intracellular Ca^(2+)homeostasis by causing mitochondrial Ca^(2+)overload due to release fromthe endoplasmic reticulum(ER).Additionally,AdipoRon promoted Ca^(2+)release from the ER by activating the PLC-IP3-IP3R pathway.The resulting mitochondrial Ca^(2+)overload enhances the anti-HCC effect when combined with chemotherapeutic drugs.Conclusions:Therefore,our study demonstrates thatAdipoRon promotesmitochondrial Ca^(2+)overload and apoptosis in HCC cells by activating the PLC-IP3-IP3R signaling pathway.AdipoRon has the potential to become an effective anti-HCC drug.
基金Supported by the National Natural Science Foundation of China(No.32172979)the Natural Science Foundation of Fujian Province(No.2021J05159)the 2023 Special Program for Promoting High-Quality Development of Marine and Fishery Industry in Fujian Province(No.PJHYF-L-2023-2)。
文摘The Fujian oyster(Crassostrea angulata) is an economically significant shellfish species distributed mainly along the Fujian coast, Southeast China. However, its genetic diversity and structure remain unclear. The main distribution area of the C. angulata is located in Fujian, South China. In total, 420 C. angulata were collected from 14 natural habitats(populations) along the Fujian coast, and their genetic diversity and structure were analyzed in the mitochondrial COI and nuclear gene ITS2 sequences. Results reveal that all the 14 populations of C. angulata exhibited high levels of genetic diversity, with a total of 57(haplotype diversity: 0.811±0.016) and 124(haplotype diversity: 0.912±0.007) haplotypes revealed by COI and ITS2, respectively. Notably, significant intermediate level of genetic differentiations between the Ningde Zhujiang(ZJ) population(FS T by COI: 0.035–0.142, P<0.05;FS T by ITS2: 0.078–0.123, P<0.05) with other populations were observed for the first time, which is also supported by the results of molecular variance analysis(FC T by COI: 0.105, P<0.05;FC T by ITS2: 0.086, P<0.05) and the clustering of the ZJ population into distinct branches in the interpopulation genetic differentiation tree. Furthermore, the evolutionary tree and haplotype network analyses do not support the formation of a clear geographical genealogical structure among these 14 populations. In addition, the population dynamics analysis suggests that the C. angulata may have undergone expansion during the third ice age of the Pleistocene. These results provide a reference for the preservation and further genetic improvement of C. angulata.
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supported by grants from National Nature Science Foundation of China(82272494,82472452,82402864)National Key R&D Program of China(2022YFC2502902)+4 种基金Key Project of Jiangsu Health Commission(K2023079)Natural Science Foundation of Jiangsu Province(BK20240368)Basic Research Pilot Project Suzhou(SSD2024062),China Postdoctoral Science Foundation(2024M762313)Boxi Youth Natural Science Foundation(BXQN2023014)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis(OA).However,the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive.In this study,we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes.Genetically overexpressing PTEN-induced putative kinase 1(PINK1)protects against cartilage degeneration by removing defective mitochondria.PINK1 knockout aggravated cartilage damage due to impaired mitophagy.SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism.Specifically,PINK1 phosphorylated PKM2 at the Ser127 site,preserving its active tetrameric form.This inhibited nuclear translocation and the interaction withβ-catenin,resulting in a metabolic shift and increased energy production.Finally,a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions.Overall,this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.
基金supported by the National Key Research and Development Program of China(2022YFC2601800)the National Natural Science Foundation of China(82472761 and 82173833)+6 种基金the Guangdong Basic and Applied Basic Research Foundation(2023B1515040006)the Key-Area Research and Development Program of Guangdong Province(2023B1111020007)the Guangzhou Science and Technology Program(2024A04J6480 and 2025A04J4549)the Guangdong Provincial Key Laboratory of Construction Foundation(2023B1212060022)the Fundamental Research Funds for the Central Universities(Sun Yat-sen University)(24xkjc018)the Basic Scientific Research Fund-Young Faculty Development Program(24qnpy184)the Shenzhen Bay Scholars Program.
文摘Mitochondria are double-membrane organelles within the cytoplasm,primarily responsible for the efficient production of ATP through oxidative phosphorylation(OXPHOS).These organelles harbor an autonomous genetic system independent of the nuclear genome,encoded by mitochondrial DNA(mtDNA).Human mitochondria contain a compact 16.6-kilobase circular genome(37 genes,13 protein-coding)that relies on over 1000 nuclear-encoded proteins for its functionality.The mtDNA forms a double-stranded structure where both the sense and antisense strands are transcribed into polycistronic precursors.The heavy(H)strand encodes 12 mRNAs,2 rRNAs,and 14 tRNAs,whereas the light(L)strand produces 1 mRNA and 8 tRNAs.These primary transcripts undergo extensive processing and maturation,including cleavage,RNA modifications,and polyadenylation,yielding functional tRNAs,rRNAs,and mRNAs.Characteristically,most mRNAs and rRNAs are interspersed with tRNA genes,which serve as recognition sites for endonucleases that process the primary transcripts into individual RNA units through site-specific cleavage at tRNA boundaries.
基金financially supported by,the Space Medical Experiment Project of China Manned Space Program(Program No.:HYZHXM01023)the National Natural Science Foundation of China(Grant No.:31870848)+1 种基金the National foreign experts project(Grant No.:G2022170026L)Key R&D Program of Shaanxi Province(Grant Nos.:2021GXLH-Z-064&2024SF-ZDCYL-03-24).
文摘Mitochondria are fundamental organelles that play a crucial role in cellular energy metabolism,substance metabolism,and various essential cellular signaling pathways.The dysfunction of mitochondria is significantly implicated in the onset and progression of aging,neurodegenerative diseases,metabolic disorders,and tumors,thereby rendering mitochondria-targeted regulation,a vital strategy for disease prevention and treatment.The recently developed mitochondrial membrane chromatography(MMC)technique,which immobilizes mitochondrial proteins as a chromatographic separation medium,has shown great potential for efficiently screening mitochondria-targeted modulators from complex compound library.In contrast to traditional screening methods,MMC has no need to purify mitochondrial proteins and can preserve its in situ and physiological conformation.Consequently,it presents broader application prospects for screening mitochondrial modulators as well as investigating receptor-ligand interactions involving any target protein associated with mitochondria.This review aims to elucidate the critical role of mitochondria in the development and progression of major chronic diseases,discuss recent advancements and applications of MMC,and propose future directions for MMC in the identification of novel mitochondrial modulators.
基金supported by the National Natural Science Foundation of China,No.81971269 (to DP)the Science and Technology Commission of Shanghai,No.YDZX20213100001003 (to DP)。
文摘In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.
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supported by the National Natural Science Foundation of China,Nos.82271222(to ZL),81971012(to ZL),82071189(to XG),and 82201335(to YL)Key Clinical Projects of Peking University Third Hospital,No.BYSYZD2019027(to ZL)。
文摘Mitochondria play an essential role in neural function,such as supporting normal energy metabolism,regulating reactive oxygen species,buffering physiological calcium loads,and maintaining the balance of morphology,subcellular distribution,and overall health through mitochondrial dynamics.Given the recent technological advances in the assessment of mitochondrial structure and functions,mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,mild cognitive impairment,and postoperative cognitive dysfunction.This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences,from the perspectives of energy metabolism,oxidative stress,calcium homeostasis,and mitochondrial dynamics(including fission-fusion,transport,and mitophagy).
基金supported by the National Natural Science Foundation of China,Nos.8247041526,81570864,82171053(to GYL)。
文摘The retina,a crucial neural tissue,is responsible for transforming light signals into visual information,a process that necessitates a significant amount of energy.Mitochondria,the primary powerhouses of the cell,play an integral role in retinal physiology by fulfilling the high-energy requirements of photoreceptors and secondary neurons through oxidative phosphorylation.In a healthy state,mitochondria ensure proper visual function by facilitating efficient conversion and transduction of visual signals.However,in retinal degenerative diseases,mitochondrial dysfunction significantly contributes to disease progression,involving a decline in membrane potential,the occurrence of DNA mutations,increased oxidative stress,and imbalances in quality-control mechanisms.These abnormalities lead to an inadequate energy supply,the exacerbation of oxidative damage,and the activation of cell death pathways,ultimately resulting in neuronal injury and dysfunction in the retina.Mitochondrial transplantation has emerged as a promising strategy for addressing these challenges.This procedure aims to restore metabolic activity and function in compromised cells through the introduction of healthy mitochondria,thereby enhancing the cellular energy production capacity and offering new strategies for the treatment of retinal degenerative diseases.Although mitochondrial transplantation presents operational and safety challenges that require further investigation,it has demonstrated potential for reviving the vitality of retinal neurons.This review offers a comprehensive examination of the principles and techniques underlying mitochondrial transplantation and its prospects for application in retinal degenerative diseases,while also delving into the associated technical and safety challenges,thereby providing references and insights for future research and treatment.
文摘The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.
