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
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
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
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
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 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
Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulp...Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.展开更多
Amborella trichopoda(Amborellaceae;hereafter simply Amborella)(Fig.1A)is a shrub endemic to New Caledonia in the Southwest Pacific that represents the sole sister species of all other extant angiosperms(Qiu et al.,199...Amborella trichopoda(Amborellaceae;hereafter simply Amborella)(Fig.1A)is a shrub endemic to New Caledonia in the Southwest Pacific that represents the sole sister species of all other extant angiosperms(Qiu et al.,1999;One Thousand Plant Transcriptomes Initiative,2019).Due to its unique phylogenetic status,it holds tremendous interest for botanists.The nuclear and mitochondrial genomes of Amborella were first published in 2013,providing valuable resources for studies on genome and gene family evolution,phylogenomics,and flower development,despite the fact that the assembly is heavily fragmented(Amborella Genome Project,2013;Rice et al.,2013).In 2024,a haplotype-resolved Amborella genome assembly was published,showing significant improvement in quality and completeness(Carey et al.,2024).展开更多
The mitochondrial DNA copy number(mtDNAcn)plays a vital role in cellular energy metabolism and mitochondrial health.As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylati...The mitochondrial DNA copy number(mtDNAcn)plays a vital role in cellular energy metabolism and mitochondrial health.As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation,maintaining an appropriate mtDNAcn level is vital for the overall cellular function.Alterations in mtDNAcn have been linked to various diseases,including neurodegenerative disorders,metabolic conditions,and cancers,making it an important biomarker for understanding the disease pathogenesis.The accurate estimation of mtDNAcn is essential for clinical applications.Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations.Clinically,mtDNAcn serves as a valuable indicator for early diagnosis,disease progression,and treatment response.For instance,in oncology,elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy.In neurodegenerative diseases such as Alzheimer’s and Parkinson’s,altered mtDNAcn patterns provide insights into disease mechanisms and progression.Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields.As research continues to uncover the implications of mtDNAcn alterations,its potential as a clinical biomarker is likely to expand,thereby enhancing our ability to diagnose and manage complex diseases.展开更多
Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and c...Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and continue to experience disease progression.Therefore,in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment.Recently,studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species(ROS)and activation of the cyclic GMP-AMP synthase(cGAS)/stimulator of interferon genes(STING)innate immunity pathways,ultimately resulting in sterile inflammation and cell death in various cells,such as cardiomyocytes and macrophages.Therefore,combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management.Notably,emerging evidence indicates that natural products targeting mitochondrial quality control(MQC)and the cGAS/STING innate immunity pathways exhibit promise in treating AMD.Here,we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways,as well as their interconnected mediators,which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses,thereby hoping to offer new insights into therapeutic interventions for AMD treatment.展开更多
The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of...The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect,as the core of energy metabolism and apoptosis regulation.Mutations in mitochondrial DNA(mtDNA)and dysregulation of mitochondrial autophagy(mitophagy)further enhance the invasive and metastatic capabilities of liver cancer.Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes,regulating calcium homeostasis,repairing mtDNA,and activating mitochondrial apoptotic pathways.Although these approaches have shown therapeutic effects,challenges persist,such as tumor heterogeneity,insufficient drug specificity,and drug resistance.Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction,development of targeted delivery systems,optimization of combination therapy regimens,and screening of biomarkers to provide new pathways for individualized treatment.With advances in technology,targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.展开更多
With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis...With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis of MASLD is complex,characterized by oxidative stress,impaired mitochondrial function and lipid metabolism,and cellular inflammation.Mitochondrial biology and function are central to the physiology of the liver.It has been suggested that mitochondrial oxidative stress plays a crucial role in MASLD progression.Excessive oxidative stress response is an important trigger for the occurrence and development of MASLD.In this review,we aim to focus on the recent advances in understanding mitochondrial oxidative stress-related mechanisms in the progression of MASLD.The in-depth elaboration of its related mechanisms is hoped to help find effective methods for treating MASLD.展开更多
Oxidation of self-stored carbohydrates and lipids provides the energy for the rapid morphogenetic transformation during asexual and infection-related development in Pyricularia oryzae,which results in intracellular ac...Oxidation of self-stored carbohydrates and lipids provides the energy for the rapid morphogenetic transformation during asexual and infection-related development in Pyricularia oryzae,which results in intracellular accumulation of reducing equivalents NADH and FADH_(2),requiring a cytosolic shuttling machinery towards mitochondria.Our previous studies identified the mitochondrial D-lactate dehydrogenase MoDld1 as a regulator to channel the metabolite flow in conjunction with redox homeostasis.However,the regulator(s)facilitating the cytosolic redox balance and the importance in propelling nutrient metabolite flow remain unknown.The G-3-P shuttle is a conserved machinery transporting the cytosolic reducing power to mitochondria.In P.oryzae,the mitochondrial G-3-P dehydrogenase Gpd2 was required for cellular NAD^(+)/NADH balance and fungal virulence.In this study,we relocate the mitochondrial G-3-P dehydrogenase Gpd2 to the cytosol for disturbing cytosolic redox status.Our results showed overexpression of cytosolic gpd2^(Δmts)without the mitochondrial targeted signal(MTS)driven by Ribosomal protein 27 promoter(PR27)exerted conflicting regulation of cellular oxidoreductase activities compared to theΔModld1 deletion mutant by RNA-seq and prevented the conidiation and pathogenicity of P.oryzae.Moreover,overexpression of gpd2^(Δmts)caused defects in glycogen and lipid mobilization underlying asexual and infectious structural development associated with decreased cellular NADH production and weakened anti-oxidation activities.RNA-seq and non-targeted metabolic profiling revealed down-regulated transcriptional activities of carbohydrate metabolism and lower abundance of fatty acids and secondary metabolites in RP27:gpd2^(Δmts).Thus,our studies indicate the essential role of cytosolic redox control in nutrient metabolism fueling the asexual and infection-related development in P.oryzae.展开更多
The pathogenesis of insulin resistance is influenced by environmental factors,genetic predispositions,and several medications.Various drugs used to managemultiple ailments have been shown to induce insulin resistance,...The pathogenesis of insulin resistance is influenced by environmental factors,genetic predispositions,and several medications.Various drugs used to managemultiple ailments have been shown to induce insulin resistance,which could lead to Type II Diabetes mellitus(T2DM).Central to drug-induced insulin resistance is mitochondrial dysfunction.Amongst disturbed pathways in drug-inducedmitochondrial toxicity is mitophagy,a process that removes dysfunctionalmitochondria through the lysosomal pathways to maintain mitochondrial quality.A balancemust always be maintained between mitochondrial dynamics and mitophagy,as any alterations may contribute to the pathogenesis of metabolic diseases such as diabetes mellitus.If damaged mitochondria are not removed,their accumulation leads to increased production of reactive oxygen species(ROS)and release of calcium and cytochrome C,which leads to apoptosis.This review paper focuses on the implications of the mitophagy initiation pathways,such as Adenosine Monophosphate-activated Protein Kinase/Mammalian Target of Rapamycin(AMPK/mTOR),PTEN-induced kinase 1,and Parkin RBR E3 ubiquitin-protein ligase,PINK/Parkin,and the receptor-mediated pathways,such as FUN14 domain containing 1(FUNDC1)and Bcl-2 interacting protein 3(BNIP3/NIX),as a crucial link between drug-induced mitochondrial dysfunction and insulin sensitivity impairment.It also focuses on the implications of mitochondrial dynamics in drug-induced insulin impairments.Pharmacological agents such as simvastatin,clarithromycin,olanzapine,and dexamethasone have been investigated and shown to induce insulin resistance in part through altered mitochondrial function.In this review paper,we further illuminate disturbances in mitophagy and mitochondrial dynamics that could also be pivotal in insulin resistance development as a result of exposure to these drugs.Mitophagy and mitochondrial dynamics remain understudied.Exploring the implications of mitophagy pathways and mitochondrial dynamics on drug-induced insulin resistance could lead to the development of new approaches that can be used to mitigate insulin resistance associated with different classes of pharmacological modalities.展开更多
Mitochondria play a crucial role in maintaining the normal physiological state of cells.Hence,ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases.Previous reviews...Mitochondria play a crucial role in maintaining the normal physiological state of cells.Hence,ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases.Previous reviews on this topic have however been inconsistencies and lack of systematic organization.Therefore,this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases.This review systematically summarizes three fundamental characteristics of mitochondrial quality control,including mitochondrial morphology and dynamics,function and metabolism,and protein expression and regulation.It also extensively examines how imbalances in mitochondrial quality are linked to major diseases,such as ischemia-hypoxia,inflammatory disorders,viral infections,metabolic dysregulations,degenerative conditions,and tumors.Additionally,the review explores innovative approaches to target mitochondrial quality control,including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality,nanomolecular materials designed for precise targeting of mitochondria,and novel cellular therapies,such as vesicle therapy and mitochondrial transplantation.This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.展开更多
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.
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.
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 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.
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.
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.
基金supported by National Natural Science Foundation of China(82272549,82472505,and 82472498)National key Research and Development plan,Ministry of Science and Technology of the People’s Republic of China(2022YFC2407203)+2 种基金the Young Health Talents of Shanghai Municipal Health Commission,China(2022YQ011)China Medical Education Association(3030537245)The Youth Talent Project of Huashan Hospital(30302164006).
文摘Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.
基金supported by the National Natural Science Foundation of China(32270217,31970205,31770211)Metasequoia funding of Nanjing Forestry University to YY。
文摘Amborella trichopoda(Amborellaceae;hereafter simply Amborella)(Fig.1A)is a shrub endemic to New Caledonia in the Southwest Pacific that represents the sole sister species of all other extant angiosperms(Qiu et al.,1999;One Thousand Plant Transcriptomes Initiative,2019).Due to its unique phylogenetic status,it holds tremendous interest for botanists.The nuclear and mitochondrial genomes of Amborella were first published in 2013,providing valuable resources for studies on genome and gene family evolution,phylogenomics,and flower development,despite the fact that the assembly is heavily fragmented(Amborella Genome Project,2013;Rice et al.,2013).In 2024,a haplotype-resolved Amborella genome assembly was published,showing significant improvement in quality and completeness(Carey et al.,2024).
文摘The mitochondrial DNA copy number(mtDNAcn)plays a vital role in cellular energy metabolism and mitochondrial health.As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation,maintaining an appropriate mtDNAcn level is vital for the overall cellular function.Alterations in mtDNAcn have been linked to various diseases,including neurodegenerative disorders,metabolic conditions,and cancers,making it an important biomarker for understanding the disease pathogenesis.The accurate estimation of mtDNAcn is essential for clinical applications.Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations.Clinically,mtDNAcn serves as a valuable indicator for early diagnosis,disease progression,and treatment response.For instance,in oncology,elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy.In neurodegenerative diseases such as Alzheimer’s and Parkinson’s,altered mtDNAcn patterns provide insights into disease mechanisms and progression.Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields.As research continues to uncover the implications of mtDNAcn alterations,its potential as a clinical biomarker is likely to expand,thereby enhancing our ability to diagnose and manage complex diseases.
基金funded by Chinese NSFC(Grant Nos.:82373336,82303238,and U22A20311,Sichuan Science and Technology Department,China(GrantNos.:2024NSFSC1945,,and 2023NSFSC0667)the Third People's Hospital of Chengdu Clinical Research Program,China(Grant Nos.:CSY-YN-01-2023-013,CSYYN-01-2023-005,and CSY-YN-03-2024-003)+1 种基金Sichuan University“From O to 1”Innovative Research Project,China(Project No.:2023SCUH0024)Health Commission of Chengdu,China(Grant No.:2024291).
文摘Age-related macular degeneration(AMD)is a disease that affects the vision of elderly individuals worldwide.Although current therapeutics have shown effectiveness against AMD,some patients may remain unresponsive and continue to experience disease progression.Therefore,in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment.Recently,studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species(ROS)and activation of the cyclic GMP-AMP synthase(cGAS)/stimulator of interferon genes(STING)innate immunity pathways,ultimately resulting in sterile inflammation and cell death in various cells,such as cardiomyocytes and macrophages.Therefore,combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management.Notably,emerging evidence indicates that natural products targeting mitochondrial quality control(MQC)and the cGAS/STING innate immunity pathways exhibit promise in treating AMD.Here,we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways,as well as their interconnected mediators,which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses,thereby hoping to offer new insights into therapeutic interventions for AMD treatment.
基金supported by the National Natural Science Foundation of China(Grant No.81860653)Qiankehe Foundation[Grant No.QN(2025)383].
文摘The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect,as the core of energy metabolism and apoptosis regulation.Mutations in mitochondrial DNA(mtDNA)and dysregulation of mitochondrial autophagy(mitophagy)further enhance the invasive and metastatic capabilities of liver cancer.Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes,regulating calcium homeostasis,repairing mtDNA,and activating mitochondrial apoptotic pathways.Although these approaches have shown therapeutic effects,challenges persist,such as tumor heterogeneity,insufficient drug specificity,and drug resistance.Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction,development of targeted delivery systems,optimization of combination therapy regimens,and screening of biomarkers to provide new pathways for individualized treatment.With advances in technology,targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.
基金supported by grants from the Top Medical Expert Team of Wuxi Taihu Talent Plan(Grant Nos.DJTD202106,GDTD202105 and YXTD202101)Medical Key Discipline Program of Wuxi Health Commission(Grant Nos.ZDXK2021007 and CXTD2021005)+1 种基金Top Talent Support Program for Young and MiddleAged People of Wuxi Health Committee(Grant No.BJ2023090)Scientific Research Program of Wuxi Health Commission(Grant Nos.Z20210 and M202208).
文摘With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis of MASLD is complex,characterized by oxidative stress,impaired mitochondrial function and lipid metabolism,and cellular inflammation.Mitochondrial biology and function are central to the physiology of the liver.It has been suggested that mitochondrial oxidative stress plays a crucial role in MASLD progression.Excessive oxidative stress response is an important trigger for the occurrence and development of MASLD.In this review,we aim to focus on the recent advances in understanding mitochondrial oxidative stress-related mechanisms in the progression of MASLD.The in-depth elaboration of its related mechanisms is hoped to help find effective methods for treating MASLD.
基金funded by the National Natural Science Foundation of China(32272513 and 31770156)the Natural Sciences and Engineering Research Council of Canada(Discovery Grant,RGPIN-2016-05356)the Canadian Foundation for Innovation(Discovery Grant,227398-2011)。
文摘Oxidation of self-stored carbohydrates and lipids provides the energy for the rapid morphogenetic transformation during asexual and infection-related development in Pyricularia oryzae,which results in intracellular accumulation of reducing equivalents NADH and FADH_(2),requiring a cytosolic shuttling machinery towards mitochondria.Our previous studies identified the mitochondrial D-lactate dehydrogenase MoDld1 as a regulator to channel the metabolite flow in conjunction with redox homeostasis.However,the regulator(s)facilitating the cytosolic redox balance and the importance in propelling nutrient metabolite flow remain unknown.The G-3-P shuttle is a conserved machinery transporting the cytosolic reducing power to mitochondria.In P.oryzae,the mitochondrial G-3-P dehydrogenase Gpd2 was required for cellular NAD^(+)/NADH balance and fungal virulence.In this study,we relocate the mitochondrial G-3-P dehydrogenase Gpd2 to the cytosol for disturbing cytosolic redox status.Our results showed overexpression of cytosolic gpd2^(Δmts)without the mitochondrial targeted signal(MTS)driven by Ribosomal protein 27 promoter(PR27)exerted conflicting regulation of cellular oxidoreductase activities compared to theΔModld1 deletion mutant by RNA-seq and prevented the conidiation and pathogenicity of P.oryzae.Moreover,overexpression of gpd2^(Δmts)caused defects in glycogen and lipid mobilization underlying asexual and infectious structural development associated with decreased cellular NADH production and weakened anti-oxidation activities.RNA-seq and non-targeted metabolic profiling revealed down-regulated transcriptional activities of carbohydrate metabolism and lower abundance of fatty acids and secondary metabolites in RP27:gpd2^(Δmts).Thus,our studies indicate the essential role of cytosolic redox control in nutrient metabolism fueling the asexual and infection-related development in P.oryzae.
文摘The pathogenesis of insulin resistance is influenced by environmental factors,genetic predispositions,and several medications.Various drugs used to managemultiple ailments have been shown to induce insulin resistance,which could lead to Type II Diabetes mellitus(T2DM).Central to drug-induced insulin resistance is mitochondrial dysfunction.Amongst disturbed pathways in drug-inducedmitochondrial toxicity is mitophagy,a process that removes dysfunctionalmitochondria through the lysosomal pathways to maintain mitochondrial quality.A balancemust always be maintained between mitochondrial dynamics and mitophagy,as any alterations may contribute to the pathogenesis of metabolic diseases such as diabetes mellitus.If damaged mitochondria are not removed,their accumulation leads to increased production of reactive oxygen species(ROS)and release of calcium and cytochrome C,which leads to apoptosis.This review paper focuses on the implications of the mitophagy initiation pathways,such as Adenosine Monophosphate-activated Protein Kinase/Mammalian Target of Rapamycin(AMPK/mTOR),PTEN-induced kinase 1,and Parkin RBR E3 ubiquitin-protein ligase,PINK/Parkin,and the receptor-mediated pathways,such as FUN14 domain containing 1(FUNDC1)and Bcl-2 interacting protein 3(BNIP3/NIX),as a crucial link between drug-induced mitochondrial dysfunction and insulin sensitivity impairment.It also focuses on the implications of mitochondrial dynamics in drug-induced insulin impairments.Pharmacological agents such as simvastatin,clarithromycin,olanzapine,and dexamethasone have been investigated and shown to induce insulin resistance in part through altered mitochondrial function.In this review paper,we further illuminate disturbances in mitophagy and mitochondrial dynamics that could also be pivotal in insulin resistance development as a result of exposure to these drugs.Mitophagy and mitochondrial dynamics remain understudied.Exploring the implications of mitophagy pathways and mitochondrial dynamics on drug-induced insulin resistance could lead to the development of new approaches that can be used to mitigate insulin resistance associated with different classes of pharmacological modalities.
基金supported by the National Natural Science Foundation of China (82272252 and 82372192)the Senior Medical Talents Program of Chongqing for Young and Middle-AgedKuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University
文摘Mitochondria play a crucial role in maintaining the normal physiological state of cells.Hence,ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases.Previous reviews on this topic have however been inconsistencies and lack of systematic organization.Therefore,this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases.This review systematically summarizes three fundamental characteristics of mitochondrial quality control,including mitochondrial morphology and dynamics,function and metabolism,and protein expression and regulation.It also extensively examines how imbalances in mitochondrial quality are linked to major diseases,such as ischemia-hypoxia,inflammatory disorders,viral infections,metabolic dysregulations,degenerative conditions,and tumors.Additionally,the review explores innovative approaches to target mitochondrial quality control,including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality,nanomolecular materials designed for precise targeting of mitochondria,and novel cellular therapies,such as vesicle therapy and mitochondrial transplantation.This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.
