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
Little is known about the inheritance of very low heteroplasmy mitochondria DNA （mtDNA） variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteropl...Little is known about the inheritance of very low heteroplasmy mitochondria DNA （mtDNA） variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteroplasmy is still about 1% due to the inherent noise level of the sequencing. In this study, we sequenced the mitochondrial genome of 44 individuals using Illumina high-throughput sequencing technology and obtained high-coverage mitochondria sequencing data. Our study population contains many mother-offspring pairs. This unique study design allows us to bypass the usual heteroplasmy limitation by analyzing the correlation of mutation levels at each position in the mtDNA sequence between maternally related pairs and non-related pairs. The study showed that very low heteroplasmy variants, down to almost 0.1%, are inherited maternally and that this inheritance begins to decrease at about 0.5%, cor- resnondin to abottleneck of about 200 mtDNA.展开更多
Objective： Leber＇s hereditary optic neuropathy （LHON） is a maternally inherited degeneration of the optic nerve caused by point mutations of mitochondrial DNA （mtDNA）. Many unsolved questions regarding the penet...Objective： Leber＇s hereditary optic neuropathy （LHON） is a maternally inherited degeneration of the optic nerve caused by point mutations of mitochondrial DNA （mtDNA）. Many unsolved questions regarding the penetrance and pathophysiological mechanism of LHON demand efficient and reliable mutation testing. This study aims to develop a minor groove binder （MGB） probe assay for rapid detection of mtDNA11778 mutation and heteroplasmy in Chinese LHON patients by real-time polymerase chain reaction （PCR）. Methods： Forty-eight patients suspected of having LHON and their maternal relatives underwent a molecular genetic evaluation, with 20 normal individuals as a control group at the same time. A real-time PCR involving two MGB probes was used to detect the mtDNA 1 1778 mutation and heteroplasmy. A linear standard curve was obtained by pUCmLHONG and pUCmLHONA clones. Results： All 48 LHON patients and their maternal relatives were positive for rntDNA11778 mutation in our assay, 27 heteroplasmic and 21 homoplasmic. Eighteen cases did not show an occurrence of the disease, while 9 developed the disease among the 27 heteroplasmic mutation cases. Eleven did not show an occurrence of the disease, while 10 cases developed the disease among 21 homoplasmic mutation cases. There was a significant difference in the incidence between the heteroplasmic and the homoplasmic mutation types. The time needed for running a real-time PCR assay was only 80 min. Conclusion： This real-time PCR assay is a rapid, reliable method for mtDNA mutation detection as well as heteroplasmy quantification. Detecting this ratio is very important for predicting phenotypic expression of unaffected carriers.展开更多
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial ...Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.展开更多
Superoxide dismutase 2(SOD2)-mediated gene therapy has significant protective effects against kanamycin-induced hearing loss and hair cell loss in the inner ear,but the underlying mechanisms are still unclear.Herein,a...Superoxide dismutase 2(SOD2)-mediated gene therapy has significant protective effects against kanamycin-induced hearing loss and hair cell loss in the inner ear,but the underlying mechanisms are still unclear.Herein,an in vivo aging model of mitochondrial DNA(mtDNA)4834 deletion mutation was established using D-galactose,and the effects of noise or kanamycin on inner ear injury was investigated.Rats subjected to mtDNA4834 mutation via D-galactose administration showed hearing loss characterized by the disruption of inner ear structure(abnormal cell morphology,hair cell lysis,and the absence of the organ of Corti),increased SOD2 promoter methylation,and an increase in the degree of apoptosis.Exposure to noise or kanamycin further contributed to the effects of D-galactose.SOD2 overexpression induced by viral injection accordingly counteracted the effects of noise and kanamycin and ameliorated the symptoms of hearing loss,suggesting the critical involvement of SOD2 in preventing deafness and hearing-related conditions.The PI3K and MAPK signaling pathways were also regulated by noise/kanamycin exposure and/or SOD2 overexpression,indicating that they may be involved in the therapeutic effect of SOD2 against age-related hearing loss.展开更多
Leukemias are a group of heterogeneous hematological malignancies driven by diverse genetic variations,and the advent of genomic sequencing technologies facilitates the investigation of genetic abnormalities in leukem...Leukemias are a group of heterogeneous hematological malignancies driven by diverse genetic variations,and the advent of genomic sequencing technologies facilitates the investigation of genetic abnormalities in leukemia.However,these sequencingbased studies mainly focus on nuclear DNAs.Increasing evidence indicates that mitochondrial dysfunction is an important mechanism of leukemia pathogenesis,which is closely related to the mitochondrial genome variations.Here,we provide an overview of current research progress concerning mitochondrial genetic variations in leukemia,encompassing gene mutations and copy number variations.We also summarize currently accessible mitochondrial DNA(mtDNA)sequencing methods.Notably,somatic mtDNA mutations may serve as natural genetic barcodes for lineage tracing and longitudinal assessment of clonal dynamics.Collectively,these findings enhance our understanding of leukemia pathogenesis and foster the identification of novel therapeutic targets and interventions.展开更多
Aim:Mutations in the mitochondrial(mt)genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells.This study explores the mutational stat...Aim:Mutations in the mitochondrial(mt)genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells.This study explores the mutational status of the mt genome of cisplatin-resistant vs.-sensitive testicular germ cell tumor(TGCT)cells and explores its association with their respiration parameters,expression of respiratory genes,and preferences for metabolic pathways to reveal new markers of therapy resistance in TGCTs.Methods:Using Illumina sequencing with Twist Enrichment Panel,the mutations of mt genomes of sensitive 2102EP,H12.1,NTERA-2,T-cam and resistant 2102EP Cis,H12.1 ODM,1411HP,1777NRpmet,NTERA-2 Cis and T-cam Cis cell lines were identified.The mt respiration of the cells was assessed using high-resolution respirometry method(O2k-respirometer Oroboros)and the differential expression profiles of mt respiratory genes were determined using RT-qPCR.Associated preferences for metabolic pathways were compared using Glycolysis/OXPHOS assay.Results:In resistant TGCT cells,new mutations in mt genes MT-ND1-6,MT-RNR,MT-CO1-3,MT-ATP6,and MT-CYB were recognized.The respiratory rates of the 1777NRpmet cell line were the highest,while those of the 1411HP line the lowest;rates of the control and all other TGCT cell lines fell between these two lines.The statistically significant differences in gene expression of the respiratory genes were recorded only in NTERA-2 Cis and T-cam Cis cell lines.Sensitive cell lines NTERA-2 and 2102EP preferred oxidative phosphorylation(OXPHOS),while glycolysis was typical for resistant NTERA-2 Cis,2102EP Cis and 1411HP cell lines.Metastatic 1777NRpmet cells seem to utilize both.An isogenic pair of cell lines H12.1 and H12.1ODM showed the opposite dependence,sensitive H12.1 preferring glycolysis,while resistant H12.1ODM OXPHOS.Conclusion:In summary,our study identified new mutations in mt genes of resistant TGCT cell lines that are associated with different mt respiration parameters,gene expression patterns and preferences for metabolic pathways,providing potential novel molecular biomarkers that distinguish the resistant TGCT phenotype or specify its histological classification.展开更多
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 the grant from the National Cancer Institute(RO1 CA104666)supported in part by the Vanderbilt-Ingram Cancer Center(P30 CA68485)
文摘Little is known about the inheritance of very low heteroplasmy mitochondria DNA （mtDNA） variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteroplasmy is still about 1% due to the inherent noise level of the sequencing. In this study, we sequenced the mitochondrial genome of 44 individuals using Illumina high-throughput sequencing technology and obtained high-coverage mitochondria sequencing data. Our study population contains many mother-offspring pairs. This unique study design allows us to bypass the usual heteroplasmy limitation by analyzing the correlation of mutation levels at each position in the mtDNA sequence between maternally related pairs and non-related pairs. The study showed that very low heteroplasmy variants, down to almost 0.1%, are inherited maternally and that this inheritance begins to decrease at about 0.5%, cor- resnondin to abottleneck of about 200 mtDNA.
基金the "Qianjiang Research Talent" grantfrom the Science and Technology Department of Zhejiang Province, China
文摘Objective： Leber＇s hereditary optic neuropathy （LHON） is a maternally inherited degeneration of the optic nerve caused by point mutations of mitochondrial DNA （mtDNA）. Many unsolved questions regarding the penetrance and pathophysiological mechanism of LHON demand efficient and reliable mutation testing. This study aims to develop a minor groove binder （MGB） probe assay for rapid detection of mtDNA11778 mutation and heteroplasmy in Chinese LHON patients by real-time polymerase chain reaction （PCR）. Methods： Forty-eight patients suspected of having LHON and their maternal relatives underwent a molecular genetic evaluation, with 20 normal individuals as a control group at the same time. A real-time PCR involving two MGB probes was used to detect the mtDNA 1 1778 mutation and heteroplasmy. A linear standard curve was obtained by pUCmLHONG and pUCmLHONA clones. Results： All 48 LHON patients and their maternal relatives were positive for rntDNA11778 mutation in our assay, 27 heteroplasmic and 21 homoplasmic. Eighteen cases did not show an occurrence of the disease, while 9 developed the disease among the 27 heteroplasmic mutation cases. Eleven did not show an occurrence of the disease, while 10 cases developed the disease among 21 homoplasmic mutation cases. There was a significant difference in the incidence between the heteroplasmic and the homoplasmic mutation types. The time needed for running a real-time PCR assay was only 80 min. Conclusion： This real-time PCR assay is a rapid, reliable method for mtDNA mutation detection as well as heteroplasmy quantification. Detecting this ratio is very important for predicting phenotypic expression of unaffected carriers.
基金supported by the European Regional Development Fund-Project MAGNET (No. CZ.02.1.01/0.0/0.0/15_003/0000492)。
文摘Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.
基金Hubei Provincial Natural Science Foundation of China(No.2014CKB511).
文摘Superoxide dismutase 2(SOD2)-mediated gene therapy has significant protective effects against kanamycin-induced hearing loss and hair cell loss in the inner ear,but the underlying mechanisms are still unclear.Herein,an in vivo aging model of mitochondrial DNA(mtDNA)4834 deletion mutation was established using D-galactose,and the effects of noise or kanamycin on inner ear injury was investigated.Rats subjected to mtDNA4834 mutation via D-galactose administration showed hearing loss characterized by the disruption of inner ear structure(abnormal cell morphology,hair cell lysis,and the absence of the organ of Corti),increased SOD2 promoter methylation,and an increase in the degree of apoptosis.Exposure to noise or kanamycin further contributed to the effects of D-galactose.SOD2 overexpression induced by viral injection accordingly counteracted the effects of noise and kanamycin and ameliorated the symptoms of hearing loss,suggesting the critical involvement of SOD2 in preventing deafness and hearing-related conditions.The PI3K and MAPK signaling pathways were also regulated by noise/kanamycin exposure and/or SOD2 overexpression,indicating that they may be involved in the therapeutic effect of SOD2 against age-related hearing loss.
文摘Leukemias are a group of heterogeneous hematological malignancies driven by diverse genetic variations,and the advent of genomic sequencing technologies facilitates the investigation of genetic abnormalities in leukemia.However,these sequencingbased studies mainly focus on nuclear DNAs.Increasing evidence indicates that mitochondrial dysfunction is an important mechanism of leukemia pathogenesis,which is closely related to the mitochondrial genome variations.Here,we provide an overview of current research progress concerning mitochondrial genetic variations in leukemia,encompassing gene mutations and copy number variations.We also summarize currently accessible mitochondrial DNA(mtDNA)sequencing methods.Notably,somatic mtDNA mutations may serve as natural genetic barcodes for lineage tracing and longitudinal assessment of clonal dynamics.Collectively,these findings enhance our understanding of leukemia pathogenesis and foster the identification of novel therapeutic targets and interventions.
基金supported by the VEGA Grant Agency of the Slovak Republic(grant no.2/0056/21)the Slovak Research and Development Agency(grant no.APVV-19-0286)Doctoral grant of the Slovak Academy of Sciences(grant no.APP0377).
文摘Aim:Mutations in the mitochondrial(mt)genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells.This study explores the mutational status of the mt genome of cisplatin-resistant vs.-sensitive testicular germ cell tumor(TGCT)cells and explores its association with their respiration parameters,expression of respiratory genes,and preferences for metabolic pathways to reveal new markers of therapy resistance in TGCTs.Methods:Using Illumina sequencing with Twist Enrichment Panel,the mutations of mt genomes of sensitive 2102EP,H12.1,NTERA-2,T-cam and resistant 2102EP Cis,H12.1 ODM,1411HP,1777NRpmet,NTERA-2 Cis and T-cam Cis cell lines were identified.The mt respiration of the cells was assessed using high-resolution respirometry method(O2k-respirometer Oroboros)and the differential expression profiles of mt respiratory genes were determined using RT-qPCR.Associated preferences for metabolic pathways were compared using Glycolysis/OXPHOS assay.Results:In resistant TGCT cells,new mutations in mt genes MT-ND1-6,MT-RNR,MT-CO1-3,MT-ATP6,and MT-CYB were recognized.The respiratory rates of the 1777NRpmet cell line were the highest,while those of the 1411HP line the lowest;rates of the control and all other TGCT cell lines fell between these two lines.The statistically significant differences in gene expression of the respiratory genes were recorded only in NTERA-2 Cis and T-cam Cis cell lines.Sensitive cell lines NTERA-2 and 2102EP preferred oxidative phosphorylation(OXPHOS),while glycolysis was typical for resistant NTERA-2 Cis,2102EP Cis and 1411HP cell lines.Metastatic 1777NRpmet cells seem to utilize both.An isogenic pair of cell lines H12.1 and H12.1ODM showed the opposite dependence,sensitive H12.1 preferring glycolysis,while resistant H12.1ODM OXPHOS.Conclusion:In summary,our study identified new mutations in mt genes of resistant TGCT cell lines that are associated with different mt respiration parameters,gene expression patterns and preferences for metabolic pathways,providing potential novel molecular biomarkers that distinguish the resistant TGCT phenotype or specify its histological classification.
