Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynth...Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.展开更多
Neurodegenerative diseases are chronic,age-related disorders characterized by a relentless,irreversible,and selective loss of neurons in motor,sensory,or cognitive systems(Gao et al.,2019).Despite their heterogeneity,...Neurodegenerative diseases are chronic,age-related disorders characterized by a relentless,irreversible,and selective loss of neurons in motor,sensory,or cognitive systems(Gao et al.,2019).Despite their heterogeneity,a common pathological feature across many of these diseases is the accumulation of aggregate-prone proteins.Particularly,the cytoplasmic aggregation in neurons of the Transactive response DNA-binding protein 43(TDP-43).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
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
Microglia are the first immune cells that are activated in the brain following ischemic stroke.Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke.Caspase activation and recruitment ...Microglia are the first immune cells that are activated in the brain following ischemic stroke.Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke.Caspase activation and recruitment domain 19(CARD19)is involved in innate immune response and inflammatory response,which are also important functions of microglia.However,the role of CARD19 in microglial biology and ischemic stroke remains unknown.Here,we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue,as well as in an in vitro model of microglial activation.Remarkably,conditional knockdown of Card19 in microglia promoted post-stroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke.Mechanistically,we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components,while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae,leading to an exaggerated pro-inflammatory response.Thus,our findings suggest that preserving mitochondrial cristae,by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra.展开更多
Modulations of mitochondrial dysfunction,which involve a series of dynamic processes such as mitochondrial biogenesis,mitochondrial fusion and fission,mitochondrial transport,mitochondrial autophagy,mitochondrial apop...Modulations of mitochondrial dysfunction,which involve a series of dynamic processes such as mitochondrial biogenesis,mitochondrial fusion and fission,mitochondrial transport,mitochondrial autophagy,mitochondrial apoptosis,and oxidative stress,play an important role in the onset and progression of stroke.With a better understanding of the critical role of mitochondrial dysfunction modulations in post-stroke neurological injury,these modulations have emerged as a potential target for stroke prevention and treatment.Additionally,since effective treatments for stroke are extremely limited and natural products currently offer some outstanding advantages,we focused on the findings and mechanisms of action related to the use of natural products for targeting mitochondrial dysfunction in the treatment of stroke.Natural products achieve neuroprotective through multi-target regulation of mitochondrial dysfunction encompassing the following processes:(1)Mitochondrial biogenesis:Cordyceps and hydroxysafflor yellow A activate the peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor pathway,promote mitochondrial DNA replication and respiratory chain protein synthesis,and thereby restore energy supply in the ischemic penumbra.(2)Mitochondrial dynamics balance:Ginsenoside Rb3 promotes Opa1-mediated neural stem cell migration and diffusion for recovery of damaged brain tissue.(3)Mitochondrial autophagy:Gypenoside XVII selectively eliminates damaged mitochondria via the phosphatase and tensin homolog-induced kinase 1/Parkin pathway and blocks reactive oxygen species and the NOD-like receptor protein 3 inflammasome cascade,thereby alleviating blood-brain barrier damage.(4)Anti-apoptotic mechanisms:Ginkgolide K inhibits Bax mitochondrial translocation and downregulates caspase-3/9 activity,reducing neuronal programmed death induced by ischemia-reperfusion.(5)Oxidative stress regulation:Scutellarin exerts antioxidant properties and improves neurological function by modulating the extracellular signal-regulated kinase 5-Kruppel-like factor 2-endothelial nitric oxide synthase signaling pathway.(6)Intercellular mitochondrial transport:Neuroprotective effects of Chrysophanol are associated with accelerated mitochondrial transfer from astrocytes to neurons.Existing studies have confirmed that natural products exhibit neuroprotective effects through multidimensional interventions targeting mitochondrial dysfunction in both ischemic and hemorrhagic stroke models.However,their clinical translation still faces challenges,such as the difficulty in standardization due to component complexity,insufficient cross-regional clinical data,and the lack of long-term safety evaluations.Future research should aim to integrate new technologies,such as single-cell sequencing and organoid models,to deeply explore the mitochondria-targeting mechanisms of natural products and validate their efficacy through multicenter clinical trials,providing theoretical support and translational pathways for the development of novel anti-stroke drugs.展开更多
Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pa...Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.展开更多
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
Chronic heart failure(CHF) remains a global health challenge with limited therapeutic options. Mitochondrial dysfunction is a key pathological feature, and traditional Chinese medicine(TCM) shows unique potential in t...Chronic heart failure(CHF) remains a global health challenge with limited therapeutic options. Mitochondrial dysfunction is a key pathological feature, and traditional Chinese medicine(TCM) shows unique potential in targeting this mechanism. Evidence from human and animal models of heart failure indicates that TCM can restore mitochondrial function by regulating mitochondrial Ca^(2+) homeostasis, oxidative stress, energy metabolism, mitochondrial dynamics, and mitophagy. TCM-based treatment of CHF offers notable clinical advantages, including improved therapeutic efficacy, enhanced cardiac function, and reduced incidence of major cardiovascular events. Experimental studies demonstrate that TCM decoctions and monomers modulate signaling pathways such as PPAR–RXRα, NF-κB, and PI3K/AKT to alleviate oxidative stress. TCM also increases AMPK activity via phosphorylation of PGC-1α, indirectly promoting mitochondrial biogenesis;attenuates calcium influx and enhances Ca^(2+) reuptake, thereby ameliorating myocardial mitochondrial dysfunction in CHF;and improves CHF by rebalancing mitochondrial dynamics and autophagy.展开更多
Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiabl...Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiable matter(USM),a composition of highly active ingredients found in walnut oil,has demonstrated antioxidant effects.This study aims to explore the neuroprotective effects of USM on d-galactose-treated C57BL/6 mice and elucidate its underlying mechanism,which was validated in PC12 cells treated with d-galactose.The results of behavioral tests demonstrated that USM significantly improved cognitive deficits associated with aging.The morphological analysis demonstrated that USM effectively alleviated hippocampal neuronal damage,synaptic impairment,and mitochondrial dysfunction induced by d-galactose.Furthermore,USM significantly increases the antioxidant enzymes activity while reducing the malondialdehyde and reactive oxygen species levels.The results suggest that USM can mitigate age-related symptoms caused by d-galactose by activating the nuclear factor erythroid-2-related factor 2 signaling pathway,which enhances the expression of antioxidant enzymes,restore redox balance,and improves synaptic and mitochondrial functions.This has a positive on improving cognition and memory disorders in elderly mice.展开更多
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
Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apo...Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis.The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA.As age advances,mitochondrial function declines progressively,which leads to an imbalance in chondrocyte energy homeostasis,partially initiating the process of cartilage degeneration.Elevated oxidative stress,impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology,with mitochondrial DNA haplogroups,particularly haplogroup J,influencing OA progression.Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases,with triphenylphosphonium(TPP)emerging as the most widely utilized molecule.Other strategies encompass Dequalinium(DQA),the Szeto-Schiller(SS)tetrapeptide family,the KLA peptide,and mitochondrial-penetrating peptides(MPP),etc.展开更多
Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in re...Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in reduced ATP synthesis,elevated reactive oxygen species(ROS)formation,and mitochondrial malfunction,which instigates oxidative stress and cellular damage,critical elements in neurodegenerative disorders like Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Alzheimer’s disease(AD).In addition to causing direct neuronal injury,rotenone significantly contributes to the activation of glial cells,specifically microglia and astrocytes.Activated microglia assumes a proinflammatory(M1)phenotype,distinguished by the secretion of inflammatory cytokines including tumor necrosis factor alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),with the generation of nitric oxide and ROS,which exacerbate the neuronal injury.Astrocytes can intensify neuroinflammation by secreting proinflammatory molecules and impairing their neuroprotective roles.Our hypothesis is that rotenone is posited to elicit a neuroinflammatory response via mitochondrial malfunction,ROS generation,and the activation of proinflammatory pathways in microglia and astrocytes.This mechanism leads to accelerated neuronal impair-ment,promoting neurodegeneration.Comprehending the inflammatory pathways activated by rotenone is crucial for pinpointing therapeutic targets to regulate glial responses and mitigate the advancement of neurodegenerative disorders linked to mitochondrial malfunction and chronic inflammation.This review examines the function of glial cells and critical inflammatory pathways,namely Nuclear factor kappaβ(NF-κB),Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin(PI3K/AKT/mTOR),and Wnt/β-catenin signaling pathway in Parkinson’s disease,Alzheimer’s disease,and ALS,emphasizing illness-specific responses and the translational constraints of rotenone-based models.The objective is to consolidate existing understanding regarding the role of rotenone-induced mitochondrial failure in promoting glial activation and neuroinflammation,highlighting the necessity for additional research into these pathways.Despite the prevalent application of rotenone in experimental models,its specific effects on glial-mediated inflammation are inadequately comprehended,necessitating further investigation to guide the formulation of targeted therapeutic strategies.展开更多
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
Choline supports phospholipid synthesis,membrane integrity,neurotransmission,verylowdensity lipoprotein export,and one-carbon/epigenetic pathways,yet most United States adults fall short of adequate intake.Fatty liver...Choline supports phospholipid synthesis,membrane integrity,neurotransmission,verylowdensity lipoprotein export,and one-carbon/epigenetic pathways,yet most United States adults fall short of adequate intake.Fatty liver is now viewed as a mitochondrial-centric metabolic-inflammatory disorder;ethanol and excess linoleic acid(LA)can magnify bioenergetic stress when choline is insufficient to sustain phosphatidylcholine/phosphatidylethanolamine.This narrative review examines whether optimized choline delivery,alongside reduced exposure to mitochondrial toxicants,offers a rational therapeutic approach.Low choline intake associates with higher liver fat and aminotransferases.In rodents,choline deficiency combined with ethanol or LA lowers mitochondrial membrane potential,limitsβ-oxidation,and promotes steatosis and inflammation.Advanced formulations-especially citicoline-demonstrate favorable absorption and tissue choline delivery and may lessen trimethylamine-N-oxide formation versus free choline salts.Early,small human studies suggest that choline repletion,together with curtailed ethanol or dietary LA,can reduce intrahepatic triglyceride content and improve insulin sensitivity,though large randomized trials are lacking.Framing fatty liver as nutrition-modifiable mitochondrial toxicosis highlights correctable choline insufficiency when the liver is burdened by ethanol or excess LA.A dual strategy-using higher-bioavailability,gutmicrobial trimethylamineNoxide-sparing choline forms and mitigating mitochondrial toxicants-targets core bioenergetic defects,may reverse early steatosis,and warrants testing in adequately powered clinical trials.展开更多
Mitochondria are central organelles in cellular metabolism,orchestrating energy production,biosynthetic pathways,and signaling networks.Nicotinamide adenine dinucleotide(NAD+)and its reduced form(NADH)are essential fo...Mitochondria are central organelles in cellular metabolism,orchestrating energy production,biosynthetic pathways,and signaling networks.Nicotinamide adenine dinucleotide(NAD+)and its reduced form(NADH)are essential for mitochondrial metabolism,functioning both as redox coenzymes and as signaling agents that help regulate cellular balance.Thus,while its major role is in energy production,NAD+is widely recognized as a metabolic cofactor and also serves as a substrate for various enzymes involved in cellular signaling,like sirtuins(SIRTs),poly(ADP-ribosyl)polymerases(PARPs),mono(ADP-ribosyl)transferases,and CD38.Sirtuins,a family of NAD+-dependent deacetylases,are critical in this regulatory network.SIRT3 removes acetyl groups from and enhances the activity of key enzymes that participate in fatty acid breakdown,the tricarboxylic acid(TCA)cycle,and the electron transport chain(etc),thereby enhancing mitochondrial efficiency and energy production.Mitochondrial NAD+biosynthesis involves multiple pathways,including the de novo synthesis from tryptophan via the kynurenine and the salvage pathway,which recycles nicotinamide back to NAD+.Moreover,NAD+concentrations influence mitochondrial dynamics such as fusion,fission,and mitophagy,which are essential for preserving mitochondrial integrity and function.NAD+alsomodulates the balance between glycolysis and oxidative phosphorylation,influencing the metabolic flexibility of cells.During NAD+depletion,mainly in metabolic disorders,cells often shift towards anaerobic glycolysis,reducing ATP production efficiency and increasing lactate production.This metabolic shift is associated with various pathophysiological conditions,including insulin resistance,neurodegeneration,and muscle wasting.This reviewexplores themultifaceted functions of NAD+in regulating mitochondrialmetabolism.It highlights the underlying causes and pathological outcomes of disrupted NAD+metabolism while exploring potential therapeutic targets and treatment strategies.展开更多
Deuterium is a heavy isotope of hydrogen,with an extra neutron,endowing it with unique biophysical and biochemical properties compared to hydrogen.The ATPase pumps in the mitochondria depend upon proton motive force t...Deuterium is a heavy isotope of hydrogen,with an extra neutron,endowing it with unique biophysical and biochemical properties compared to hydrogen.The ATPase pumps in the mitochondria depend upon proton motive force to catalyze the reaction that produces ATP.Deuterons disrupt the pumps,inducing excessive reactive oxygen species and decreased ATP synthesis.The aim of this review is to develop a theory that mitochondrial dysfunction due to deuterium overload,systemically,is a primary cause of Parkinson’s disease(PD).The gut microbes supply deuterium-depleted short chain fatty acids(SCFAs)to the colonocytes,particularly butyrate,and an insufficient supply of butyrate may be a primary driver behind mitochondrial dysfunction in the gut,an early factor in PD.Indeed,low gut butyrate is a characteristic feature of PD.Mitochondrial dysfunction is a factor in many diseases,including all neurodegenerative diseases.Biological organisms have devised sophisticated strategies for protecting the ATPase pumps from deuterium overload.One such strategy may involve capturing deuterons in bis-allylic carbon atoms present in polyunsaturated fatty acids(PUFAs)in cardiolipin.Cardiolipin uniquely localizes to the inner membrane of the intermembrane space,tightly integrated into ATPase proteins.Bis-allylic carbon atoms can capture and retain deuterium,and,interestingly,deuterium doping in PUFAs can quench the chain reaction that causes massive damage upon lipid peroxidation.Neuronal cardiolipin is especially rich in docosahexaenoic acid(DHA),a PUFA with five bisallylic carbon atoms.Upon excessive oxidative stress,cardiolipin migrates to the outer membrane,where it interacts withα-synuclein(α-syn),the amyloidogenic protein that accumulates as fibrils in Lewy bodies in association with PD.Such interaction leads to pore formation and the launch of an apoptotic cascade.α-syn misfolding likely begins in the gut,and misfoldedα-syn travels along nerve fibers,particularly the vagus nerve,to reach the brainstem nuclei,where it can seed misfolding ofα-syn molecules already present there.Mitochondrial dysfunction in the gut may be a primary factor in PD,and low-deuterium nutrients may be therapeutic.展开更多
Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular ...Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.展开更多
Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and ...Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and pulmonary vascular remodeling,rise with disease severity,and may contribute to the excess cardiovascular risk—although effect sizes and causality remain uncertain.This review centers on the homocysteine–carnitine relationship in COPD pathophysiology.Carnitine deficiency,prevalent in COPD,can worsen mitochondrial bioenergetics,promote accumulation of acyl intermediates,and reduce nitric oxide bioavailability via endothelial nitric oxide synthase uncoupling(eNOS).Conversely,restoring carnitine status in experimental and early clinical settings has been associated with lower homocysteine,improved nitric oxide signaling,and attenuation of vascular remodeling,suggesting a reciprocal link rather than a one-way pathway.We review existing evidence on various COPD phenotypes and severities,delineate mechanisms that connect homocysteine,carnitine metabolism,mitochondria,redox balance and eNOS uncoupling,and evaluate therapeutic strategies—ranging from lowering homocysteine with B-group vitamins to integrated approaches that also supportmitochondrial function and redox homeostasis,including targeted carnitine supplementation.The role of L-carnitine as a potential therapeutic agent for lowering homocysteine and improving mitochondrial and vascular function warrants further investigation,as it may help slow the progression of COPD and its related comorbidities.展开更多
文摘Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.
基金funded by the“Instituto de Salud Carlos III”(PI 17-000134,PI 20-0155,PI23/00176)the“Diputaciode Lleida”(PP10601-PIRS2021)to MPO+2 种基金Also from the“Diputaciode Lleida”(PP10605-PIRS2021)the“Generalitat de Catalunya”:Agency for Management of University and Research Grants(2021SGR00990)to RPSupport was also received in the form of a FUNDELA Grant,“RedELA-Plataforma Investigacion”and the“Fundacio Miquel Valls”(Jack Van den Hoek donation)(to MPO)。
文摘Neurodegenerative diseases are chronic,age-related disorders characterized by a relentless,irreversible,and selective loss of neurons in motor,sensory,or cognitive systems(Gao et al.,2019).Despite their heterogeneity,a common pathological feature across many of these diseases is the accumulation of aggregate-prone proteins.Particularly,the cytoplasmic aggregation in neurons of the Transactive response DNA-binding protein 43(TDP-43).
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.
文摘Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors,shaping the dynamic landscape of the developing brain.A major component of the developing brain that enables this dynamic is the white matter(WM),known to be affected in neurodevelopmental disorders(NDDs)(Rokach et al.,2024).WM formation is mediated by myelination,a multifactorial process driven by neuro-glia interactions dependent on proper neuronal functionality(Simons and Trajkovic,2006).Another key aspect of neurodevelopmental abnormalities involves neuronal dynamics and function,with recent advances significantly enhancing our understanding of both neuronal and glial mitochondrial function(Devine and Kittler,2018;Rojas-Charry et al.,2021).Energy homeostasis in neurons,attributed largely to mitochondrial function,is critical for proper functionality and interactions with oligodendrocytes(OLs),the cells forming myelin in the brain’s WM.We herein discuss the interplay between these processes and speculate on potential dysfunction in NDDs.
基金National Natural Science Foundation of China,Nos.81920108017(to YX),82401546(to HL)Jiangsu Province Key Medical Discipline,No.ZDXK202216(to YX)the Key Research and Development Program of Jiangsu Province of China,No.BE2020620(to YX).
文摘Microglia are the first immune cells that are activated in the brain following ischemic stroke.Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke.Caspase activation and recruitment domain 19(CARD19)is involved in innate immune response and inflammatory response,which are also important functions of microglia.However,the role of CARD19 in microglial biology and ischemic stroke remains unknown.Here,we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue,as well as in an in vitro model of microglial activation.Remarkably,conditional knockdown of Card19 in microglia promoted post-stroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke.Mechanistically,we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components,while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae,leading to an exaggerated pro-inflammatory response.Thus,our findings suggest that preserving mitochondrial cristae,by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra.
基金supported by the National Natural Science Foundation of China,No.82204663(to TZ)the Natural Science Foundation of Shandong Province,No.ZR2022QH058(to TZ).
文摘Modulations of mitochondrial dysfunction,which involve a series of dynamic processes such as mitochondrial biogenesis,mitochondrial fusion and fission,mitochondrial transport,mitochondrial autophagy,mitochondrial apoptosis,and oxidative stress,play an important role in the onset and progression of stroke.With a better understanding of the critical role of mitochondrial dysfunction modulations in post-stroke neurological injury,these modulations have emerged as a potential target for stroke prevention and treatment.Additionally,since effective treatments for stroke are extremely limited and natural products currently offer some outstanding advantages,we focused on the findings and mechanisms of action related to the use of natural products for targeting mitochondrial dysfunction in the treatment of stroke.Natural products achieve neuroprotective through multi-target regulation of mitochondrial dysfunction encompassing the following processes:(1)Mitochondrial biogenesis:Cordyceps and hydroxysafflor yellow A activate the peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor pathway,promote mitochondrial DNA replication and respiratory chain protein synthesis,and thereby restore energy supply in the ischemic penumbra.(2)Mitochondrial dynamics balance:Ginsenoside Rb3 promotes Opa1-mediated neural stem cell migration and diffusion for recovery of damaged brain tissue.(3)Mitochondrial autophagy:Gypenoside XVII selectively eliminates damaged mitochondria via the phosphatase and tensin homolog-induced kinase 1/Parkin pathway and blocks reactive oxygen species and the NOD-like receptor protein 3 inflammasome cascade,thereby alleviating blood-brain barrier damage.(4)Anti-apoptotic mechanisms:Ginkgolide K inhibits Bax mitochondrial translocation and downregulates caspase-3/9 activity,reducing neuronal programmed death induced by ischemia-reperfusion.(5)Oxidative stress regulation:Scutellarin exerts antioxidant properties and improves neurological function by modulating the extracellular signal-regulated kinase 5-Kruppel-like factor 2-endothelial nitric oxide synthase signaling pathway.(6)Intercellular mitochondrial transport:Neuroprotective effects of Chrysophanol are associated with accelerated mitochondrial transfer from astrocytes to neurons.Existing studies have confirmed that natural products exhibit neuroprotective effects through multidimensional interventions targeting mitochondrial dysfunction in both ischemic and hemorrhagic stroke models.However,their clinical translation still faces challenges,such as the difficulty in standardization due to component complexity,insufficient cross-regional clinical data,and the lack of long-term safety evaluations.Future research should aim to integrate new technologies,such as single-cell sequencing and organoid models,to deeply explore the mitochondria-targeting mechanisms of natural products and validate their efficacy through multicenter clinical trials,providing theoretical support and translational pathways for the development of novel anti-stroke drugs.
基金supported by grants from Collaborative Research Fund(Ref:C4032-21GF)General Research Grant(Ref:14114822)+1 种基金Group Research Scheme(Ref:3110146)Area of Excellence(Ref:Ao E/M-402/20)。
文摘Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.
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 the National Natural Science Foundation of China (No. 82374195)。
文摘Chronic heart failure(CHF) remains a global health challenge with limited therapeutic options. Mitochondrial dysfunction is a key pathological feature, and traditional Chinese medicine(TCM) shows unique potential in targeting this mechanism. Evidence from human and animal models of heart failure indicates that TCM can restore mitochondrial function by regulating mitochondrial Ca^(2+) homeostasis, oxidative stress, energy metabolism, mitochondrial dynamics, and mitophagy. TCM-based treatment of CHF offers notable clinical advantages, including improved therapeutic efficacy, enhanced cardiac function, and reduced incidence of major cardiovascular events. Experimental studies demonstrate that TCM decoctions and monomers modulate signaling pathways such as PPAR–RXRα, NF-κB, and PI3K/AKT to alleviate oxidative stress. TCM also increases AMPK activity via phosphorylation of PGC-1α, indirectly promoting mitochondrial biogenesis;attenuates calcium influx and enhances Ca^(2+) reuptake, thereby ameliorating myocardial mitochondrial dysfunction in CHF;and improves CHF by rebalancing mitochondrial dynamics and autophagy.
基金supported by the National Key Research and Development Program(2022YFD1600402)Hebei Provincial Major Science and Technology Achievement Transformation Project(21287101Z)Hebei Provincial Innovation and Entrepreneurship Team Project(215A7102D)。
文摘Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiable matter(USM),a composition of highly active ingredients found in walnut oil,has demonstrated antioxidant effects.This study aims to explore the neuroprotective effects of USM on d-galactose-treated C57BL/6 mice and elucidate its underlying mechanism,which was validated in PC12 cells treated with d-galactose.The results of behavioral tests demonstrated that USM significantly improved cognitive deficits associated with aging.The morphological analysis demonstrated that USM effectively alleviated hippocampal neuronal damage,synaptic impairment,and mitochondrial dysfunction induced by d-galactose.Furthermore,USM significantly increases the antioxidant enzymes activity while reducing the malondialdehyde and reactive oxygen species levels.The results suggest that USM can mitigate age-related symptoms caused by d-galactose by activating the nuclear factor erythroid-2-related factor 2 signaling pathway,which enhances the expression of antioxidant enzymes,restore redox balance,and improves synaptic and mitochondrial functions.This has a positive on improving cognition and memory disorders in elderly mice.
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 the Science and Technology Program of Guangzhou(202206010140)the Guangdong Provincial Key Research and Development Program(2023B1111050003).
文摘Osteoarthritis(OA)is a degenerative joint disease associated with age,prominently marked by articular cartilage degradation.In OA cartilage,the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis.The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA.As age advances,mitochondrial function declines progressively,which leads to an imbalance in chondrocyte energy homeostasis,partially initiating the process of cartilage degeneration.Elevated oxidative stress,impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology,with mitochondrial DNA haplogroups,particularly haplogroup J,influencing OA progression.Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases,with triphenylphosphonium(TPP)emerging as the most widely utilized molecule.Other strategies encompass Dequalinium(DQA),the Szeto-Schiller(SS)tetrapeptide family,the KLA peptide,and mitochondrial-penetrating peptides(MPP),etc.
文摘Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in reduced ATP synthesis,elevated reactive oxygen species(ROS)formation,and mitochondrial malfunction,which instigates oxidative stress and cellular damage,critical elements in neurodegenerative disorders like Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Alzheimer’s disease(AD).In addition to causing direct neuronal injury,rotenone significantly contributes to the activation of glial cells,specifically microglia and astrocytes.Activated microglia assumes a proinflammatory(M1)phenotype,distinguished by the secretion of inflammatory cytokines including tumor necrosis factor alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),with the generation of nitric oxide and ROS,which exacerbate the neuronal injury.Astrocytes can intensify neuroinflammation by secreting proinflammatory molecules and impairing their neuroprotective roles.Our hypothesis is that rotenone is posited to elicit a neuroinflammatory response via mitochondrial malfunction,ROS generation,and the activation of proinflammatory pathways in microglia and astrocytes.This mechanism leads to accelerated neuronal impair-ment,promoting neurodegeneration.Comprehending the inflammatory pathways activated by rotenone is crucial for pinpointing therapeutic targets to regulate glial responses and mitigate the advancement of neurodegenerative disorders linked to mitochondrial malfunction and chronic inflammation.This review examines the function of glial cells and critical inflammatory pathways,namely Nuclear factor kappaβ(NF-κB),Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin(PI3K/AKT/mTOR),and Wnt/β-catenin signaling pathway in Parkinson’s disease,Alzheimer’s disease,and ALS,emphasizing illness-specific responses and the translational constraints of rotenone-based models.The objective is to consolidate existing understanding regarding the role of rotenone-induced mitochondrial failure in promoting glial activation and neuroinflammation,highlighting the necessity for additional research into these pathways.Despite the prevalent application of rotenone in experimental models,its specific effects on glial-mediated inflammation are inadequately comprehended,necessitating further investigation to guide the formulation of targeted therapeutic strategies.
基金supported by 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.
文摘Choline supports phospholipid synthesis,membrane integrity,neurotransmission,verylowdensity lipoprotein export,and one-carbon/epigenetic pathways,yet most United States adults fall short of adequate intake.Fatty liver is now viewed as a mitochondrial-centric metabolic-inflammatory disorder;ethanol and excess linoleic acid(LA)can magnify bioenergetic stress when choline is insufficient to sustain phosphatidylcholine/phosphatidylethanolamine.This narrative review examines whether optimized choline delivery,alongside reduced exposure to mitochondrial toxicants,offers a rational therapeutic approach.Low choline intake associates with higher liver fat and aminotransferases.In rodents,choline deficiency combined with ethanol or LA lowers mitochondrial membrane potential,limitsβ-oxidation,and promotes steatosis and inflammation.Advanced formulations-especially citicoline-demonstrate favorable absorption and tissue choline delivery and may lessen trimethylamine-N-oxide formation versus free choline salts.Early,small human studies suggest that choline repletion,together with curtailed ethanol or dietary LA,can reduce intrahepatic triglyceride content and improve insulin sensitivity,though large randomized trials are lacking.Framing fatty liver as nutrition-modifiable mitochondrial toxicosis highlights correctable choline insufficiency when the liver is burdened by ethanol or excess LA.A dual strategy-using higher-bioavailability,gutmicrobial trimethylamineNoxide-sparing choline forms and mitigating mitochondrial toxicants-targets core bioenergetic defects,may reverse early steatosis,and warrants testing in adequately powered clinical trials.
基金A fellowship support from the Golda Meir Fellowship Fund,The Hebrew University of Jerusalem,Israel。
文摘Mitochondria are central organelles in cellular metabolism,orchestrating energy production,biosynthetic pathways,and signaling networks.Nicotinamide adenine dinucleotide(NAD+)and its reduced form(NADH)are essential for mitochondrial metabolism,functioning both as redox coenzymes and as signaling agents that help regulate cellular balance.Thus,while its major role is in energy production,NAD+is widely recognized as a metabolic cofactor and also serves as a substrate for various enzymes involved in cellular signaling,like sirtuins(SIRTs),poly(ADP-ribosyl)polymerases(PARPs),mono(ADP-ribosyl)transferases,and CD38.Sirtuins,a family of NAD+-dependent deacetylases,are critical in this regulatory network.SIRT3 removes acetyl groups from and enhances the activity of key enzymes that participate in fatty acid breakdown,the tricarboxylic acid(TCA)cycle,and the electron transport chain(etc),thereby enhancing mitochondrial efficiency and energy production.Mitochondrial NAD+biosynthesis involves multiple pathways,including the de novo synthesis from tryptophan via the kynurenine and the salvage pathway,which recycles nicotinamide back to NAD+.Moreover,NAD+concentrations influence mitochondrial dynamics such as fusion,fission,and mitophagy,which are essential for preserving mitochondrial integrity and function.NAD+alsomodulates the balance between glycolysis and oxidative phosphorylation,influencing the metabolic flexibility of cells.During NAD+depletion,mainly in metabolic disorders,cells often shift towards anaerobic glycolysis,reducing ATP production efficiency and increasing lactate production.This metabolic shift is associated with various pathophysiological conditions,including insulin resistance,neurodegeneration,and muscle wasting.This reviewexplores themultifaceted functions of NAD+in regulating mitochondrialmetabolism.It highlights the underlying causes and pathological outcomes of disrupted NAD+metabolism while exploring potential therapeutic targets and treatment strategies.
基金funded in part by Quanta Computer,Inc.,in Tanyuan,Taiwan,under contract number 6950759,as part of the AIR project.
文摘Deuterium is a heavy isotope of hydrogen,with an extra neutron,endowing it with unique biophysical and biochemical properties compared to hydrogen.The ATPase pumps in the mitochondria depend upon proton motive force to catalyze the reaction that produces ATP.Deuterons disrupt the pumps,inducing excessive reactive oxygen species and decreased ATP synthesis.The aim of this review is to develop a theory that mitochondrial dysfunction due to deuterium overload,systemically,is a primary cause of Parkinson’s disease(PD).The gut microbes supply deuterium-depleted short chain fatty acids(SCFAs)to the colonocytes,particularly butyrate,and an insufficient supply of butyrate may be a primary driver behind mitochondrial dysfunction in the gut,an early factor in PD.Indeed,low gut butyrate is a characteristic feature of PD.Mitochondrial dysfunction is a factor in many diseases,including all neurodegenerative diseases.Biological organisms have devised sophisticated strategies for protecting the ATPase pumps from deuterium overload.One such strategy may involve capturing deuterons in bis-allylic carbon atoms present in polyunsaturated fatty acids(PUFAs)in cardiolipin.Cardiolipin uniquely localizes to the inner membrane of the intermembrane space,tightly integrated into ATPase proteins.Bis-allylic carbon atoms can capture and retain deuterium,and,interestingly,deuterium doping in PUFAs can quench the chain reaction that causes massive damage upon lipid peroxidation.Neuronal cardiolipin is especially rich in docosahexaenoic acid(DHA),a PUFA with five bisallylic carbon atoms.Upon excessive oxidative stress,cardiolipin migrates to the outer membrane,where it interacts withα-synuclein(α-syn),the amyloidogenic protein that accumulates as fibrils in Lewy bodies in association with PD.Such interaction leads to pore formation and the launch of an apoptotic cascade.α-syn misfolding likely begins in the gut,and misfoldedα-syn travels along nerve fibers,particularly the vagus nerve,to reach the brainstem nuclei,where it can seed misfolding ofα-syn molecules already present there.Mitochondrial dysfunction in the gut may be a primary factor in PD,and low-deuterium nutrients may be therapeutic.
文摘Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.
基金financed by the Ryazan StateMedical University intra-university grant:Agreement No.1A/25 for the implementation of research on the topic:“Metabolic Markers of Impaired Adaptation to Hypoxia in COPD:The Role of Hyperhomocysteinemia and Carnitine Deficiency”dated 09 April 2025.
文摘Elevated homocysteine is a clinically relevantmetabolic signal in chronic obstructive pulmonary disease(COPD).Higher circulating levels track with oxidative stress,endothelial dysfunction,mitochondrial impairment,and pulmonary vascular remodeling,rise with disease severity,and may contribute to the excess cardiovascular risk—although effect sizes and causality remain uncertain.This review centers on the homocysteine–carnitine relationship in COPD pathophysiology.Carnitine deficiency,prevalent in COPD,can worsen mitochondrial bioenergetics,promote accumulation of acyl intermediates,and reduce nitric oxide bioavailability via endothelial nitric oxide synthase uncoupling(eNOS).Conversely,restoring carnitine status in experimental and early clinical settings has been associated with lower homocysteine,improved nitric oxide signaling,and attenuation of vascular remodeling,suggesting a reciprocal link rather than a one-way pathway.We review existing evidence on various COPD phenotypes and severities,delineate mechanisms that connect homocysteine,carnitine metabolism,mitochondria,redox balance and eNOS uncoupling,and evaluate therapeutic strategies—ranging from lowering homocysteine with B-group vitamins to integrated approaches that also supportmitochondrial function and redox homeostasis,including targeted carnitine supplementation.The role of L-carnitine as a potential therapeutic agent for lowering homocysteine and improving mitochondrial and vascular function warrants further investigation,as it may help slow the progression of COPD and its related comorbidities.
