The concept that ＂Exercise is Medicine＂ has been challenged by the rising prevalence of non-communicable chronic diseases （NCDs）. This is partly due to the fact that the underlying mechanisms of how exercise influ...The concept that ＂Exercise is Medicine＂ has been challenged by the rising prevalence of non-communicable chronic diseases （NCDs）. This is partly due to the fact that the underlying mechanisms of how exercise influences energy homeostasis and counteracts high-fat diets and physical inactivity is complex and remains relatively poorly understood on a molecular level. In addition to genetic polymorphisms in humans that lead to gross variations in responsiveness to exercise, adaptation in mitochondrial networks is central to physical activity, inactivity, and diet. To harness the benefits of exercise for NCDs, much work still needs to be done to improve health effectively on a societal level such as developing personalized exercise interventions aided by advances in high-throughput genomics, proteomics, and metabolomics. We propose that understanding the mitochondrial phenotype according to the molecular information of genotypes, lifestyles, and exercise responsiveness in individuals will optimize exercise effects for prevention of NCDs.展开更多
Leber’s hereditary optic neuropathy(LHON)is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA(mtDNA).Unfortunately,the available treatment options for LHON patients are limited due t...Leber’s hereditary optic neuropathy(LHON)is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA(mtDNA).Unfortunately,the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement.In our study,we reprogramming LHON urine cells into induced pluripotent stem cells(iPSCs)and differentiating them into neural progenitor cells(NPCs)and neurons for disease modeling.Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function,confirming the disease phenotype.However,through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells(MSCs),we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons.These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs,even after their differentiation into neurons.This discovery holds promise as a potential therapeutic strategy for LHON patients.展开更多
Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether m...Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis.展开更多
Delayed recovery from ulcerative colitis is mainly due to impaired healing of the intestinal epithelium after inflammation.The circadian rhythmcontrols cell proliferation and energy metabolism.However,the role of circ...Delayed recovery from ulcerative colitis is mainly due to impaired healing of the intestinal epithelium after inflammation.The circadian rhythmcontrols cell proliferation and energy metabolism.However,the role of circadian genes in inflammatory bowel disease is largely unknown.The purpose of this study was to investigate whether disrupting the circadian rhythm in mice can worsen colitis by altering mitochondrial energy metabolism.Mice in the experimental groups were under physiologic stress with an 8-h light shift jet-lag schedule every 3 days,whereas those in the control group were not.Subsequently,half of the mice in the control and jet-lagged groups were given dextran sodium sulfate(DSS)to induce colitis.Mice in each group were euthanized at zeitgeber time(ZT)0,ZT4,ZT8,ZT12,ZT16,and ZT20.To investigate the effects of jet lag on the mice,colon specimens were subjected to hematoxylin and eosin staining to analyse mRNA and protein expression of core circadian clock genes(Bmal1,Clock,Per1,Per2,Cry1,Cry2,and Nr1d1).We analysed the mitochondrial morphology,adenosine triphosphate(ATP)levels,and the expression of dynamin-related protein 1(Drp1)and ser637-phosphorylated(p)-Drp1,which are closely related to ATP production.We further investigated the effect of PER2 knockdown in the colon epithelial cells(CCD 841 CoN)by measuring ATP and cell proliferation levels.Disrupting the circadian rhythm changed the oscillation of clock genes in the colon of mice,altered the mitochondrial morphology of the colon specimens,decreased the expression of p-Drp1,reduced ATP production,and exacerbated inflammatory responses in mice with DSS-induced colitis.Additionally,silencing of PER2 in the colon epithelial cells reduced ATP production and cell proliferation.Disrupting the circadian rhythm in mice decreases mitochondrial energy metabolism in the colon and exacerbates symptoms of colitis.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.31300977,31171142)Shanghai Pujiang Program(No.15PJC032)the Key Laboratory Construction Project of Adolescent Health Assessment and Exercise Intervention of Ministry of Education,China(No.40500-541235-14203/004)
文摘The concept that ＂Exercise is Medicine＂ has been challenged by the rising prevalence of non-communicable chronic diseases （NCDs）. This is partly due to the fact that the underlying mechanisms of how exercise influences energy homeostasis and counteracts high-fat diets and physical inactivity is complex and remains relatively poorly understood on a molecular level. In addition to genetic polymorphisms in humans that lead to gross variations in responsiveness to exercise, adaptation in mitochondrial networks is central to physical activity, inactivity, and diet. To harness the benefits of exercise for NCDs, much work still needs to be done to improve health effectively on a societal level such as developing personalized exercise interventions aided by advances in high-throughput genomics, proteomics, and metabolomics. We propose that understanding the mitochondrial phenotype according to the molecular information of genotypes, lifestyles, and exercise responsiveness in individuals will optimize exercise effects for prevention of NCDs.
基金financially supported by the National Key Research and Development Program of China(2022YFE0210100,2023YFE0210100,2022YFA1103800,2019YFA0904500)the National Natural Science Foundation projects of China(32025010,92157202,32241002,92254301,92357302,32261160376,31970709,32070729,32100619,32170747,32322022,32370782,32371007,32300608,32300620)+8 种基金NSFC/RGC Joint Grant Scheme 2022/2023(N_CUHK 428/22)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0480000)the Key Research Program,CAS(ZDBS-ZRKJZ-TLC003)International Cooperation Program,CAS(154144KYSB20200006)CAS Project for Young Scientists in Basic Research(YSBR-075)Guangdong Province Science and Technology Program(2023B0303000023,2023B1111050005,2023A1515030231,2022A1515110493,2023B1212060050,2021A1515012513,2021B1515020096,2022A1515012616,2022A1515110951,2023B1212120009,2024A1515010782,2024B1515040020,2024A1515030120)Guangzhou Science and Technology Program(202102021037,202102020827,202102080066,202206060002,2023A04J0414)Health@InnoHK funding support from the Innovation Technology Commission of the Hong Kong SAR,Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of SciencesCAS Youth Innovation Promotion Association(to Y.W and K.C).
文摘Leber’s hereditary optic neuropathy(LHON)is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA(mtDNA).Unfortunately,the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement.In our study,we reprogramming LHON urine cells into induced pluripotent stem cells(iPSCs)and differentiating them into neural progenitor cells(NPCs)and neurons for disease modeling.Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function,confirming the disease phenotype.However,through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells(MSCs),we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons.These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs,even after their differentiation into neurons.This discovery holds promise as a potential therapeutic strategy for LHON patients.
基金National Natural Science Foundation of China,Grant/Award Numbers:82072722,81830070,81772935,81672340StateKey Laboratory ofCancer Biology Project,Grant/Award Number:CBSKL2019ZZ26。
文摘Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis.
基金supported by National Key R&D Program of China[No.2018YFC0114600]National Natural Science Foundation of China[No.82170547,No.81873558].
文摘Delayed recovery from ulcerative colitis is mainly due to impaired healing of the intestinal epithelium after inflammation.The circadian rhythmcontrols cell proliferation and energy metabolism.However,the role of circadian genes in inflammatory bowel disease is largely unknown.The purpose of this study was to investigate whether disrupting the circadian rhythm in mice can worsen colitis by altering mitochondrial energy metabolism.Mice in the experimental groups were under physiologic stress with an 8-h light shift jet-lag schedule every 3 days,whereas those in the control group were not.Subsequently,half of the mice in the control and jet-lagged groups were given dextran sodium sulfate(DSS)to induce colitis.Mice in each group were euthanized at zeitgeber time(ZT)0,ZT4,ZT8,ZT12,ZT16,and ZT20.To investigate the effects of jet lag on the mice,colon specimens were subjected to hematoxylin and eosin staining to analyse mRNA and protein expression of core circadian clock genes(Bmal1,Clock,Per1,Per2,Cry1,Cry2,and Nr1d1).We analysed the mitochondrial morphology,adenosine triphosphate(ATP)levels,and the expression of dynamin-related protein 1(Drp1)and ser637-phosphorylated(p)-Drp1,which are closely related to ATP production.We further investigated the effect of PER2 knockdown in the colon epithelial cells(CCD 841 CoN)by measuring ATP and cell proliferation levels.Disrupting the circadian rhythm changed the oscillation of clock genes in the colon of mice,altered the mitochondrial morphology of the colon specimens,decreased the expression of p-Drp1,reduced ATP production,and exacerbated inflammatory responses in mice with DSS-induced colitis.Additionally,silencing of PER2 in the colon epithelial cells reduced ATP production and cell proliferation.Disrupting the circadian rhythm in mice decreases mitochondrial energy metabolism in the colon and exacerbates symptoms of colitis.
