The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance ...The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance between protein synthesis and degradation,is essential for cell functions during plant growth,development,and stress resistance.Nucleus-encoded chloroplast-and mitochondrion-targeted proteins and ER-resident proteins are imported from the cytosol and undergo modification and maturation within their respective organelles.Protein folding is an error-prone process that is influenced by both developmental signals and environmental cues;a number of mechanisms have evolved to ensure efficient import and proper folding and maturation of proteins in plant organelles.Misfolded or damaged proteins with nonnative conformations are subject to degradation via complementary or competing pathways:intraorganelle proteases,the organelle-associated ubiquitin-proteasome system,and the selective autophagy of partial or entire organelles.When proteins in nonnative conformations accumulate,the organellespecific unfolded protein response operates to restore protein homeostasis by reducing protein folding demand,increasing protein folding capacity,and enhancing components involved in proteasome-associated protein degradation and autophagy.This review summarizes recent progress on the understanding of protein quality control in the ER,chloroplasts,and mitochondria in plants,with a focus on common mechanisms shared by these organelles during protein homeostasis.展开更多
Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability o...Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability or dysfunction may be the key stimulating factors to activate NLRP3 inflammasome,and sustained Ca^(2+)transfer can result in mitochondrial dysfunction.We focused on KCs to explore the damage to mitochondria by EA.After EA stimulation,cells produced an oxidative stress(OS)response with a significant increase in ROS release.Immunoprecipitation experiments and the addition of inhibitors revealed that the increase in the level of intracellular Ca^(2+)led to Ca^(2+)accumulation in the mitochondrial matrix via mitochondria-associated membranes(MAMs).This was accompanied by a significant release of m ROS,loss of MMP and ATP,and a significant increase in mitochondrial permeability transition pore opening,ultimately leading to mitochondrial instability.These findings confirmed the mechanism that EA induced mitochondrial Ca^(2+)imbalance in KCs via MAM,ultimately leading to mitochondrial dysfunction.Meanwhile,EA induced OS and the decrease of MMP and ATP in rat liver,and significant lesions were found in liver mitochondria.Swelling of the inner mitochondrial cristae and mitochondrial vacuolization occurred,with a marked increase in lipid droplets.展开更多
The endoplasmic reticulum(ER)is connected to mitochondria through mitochondria-associated ER membranes(MAMs).MAMs provide a framework for crosstalk between the ER and mitochondria,playing a crucial role in regulating ...The endoplasmic reticulum(ER)is connected to mitochondria through mitochondria-associated ER membranes(MAMs).MAMs provide a framework for crosstalk between the ER and mitochondria,playing a crucial role in regulating cellular calcium balance,lipid metabolism,and cell death.Dysregulation of MAMs is involved in the development of chronic liver disease(CLD).In CLD,changes in MAMs structure and function occur due to factors such as cellular stress,inflammation,and oxidative stress,leading to abnormal interactions between mitochondria and the ER,resulting in liver cell injury,fibrosis,and impaired liver function.Traditional Chinese medicine has shown some research progress in regulating MAMs signaling and treating CLD.This paper reviews the literature on the association between mitochondria and the ER,as well as the intervention of traditional Chinese medicine in regulating CLD.展开更多
Endoplasmic reticulum(ER)and mitochondria are tubular organelles with a characteristic“network structure”that facilitates the formation of inter-organellar connections.As a result,mitochondria-associated ER membrane...Endoplasmic reticulum(ER)and mitochondria are tubular organelles with a characteristic“network structure”that facilitates the formation of inter-organellar connections.As a result,mitochondria-associated ER membranes(MAMs),a subdomain of the ER that is tightly linked to and communicates with mitochondria,serve multiple physiological functions including lipid synthesis and exchange,calcium signaling,bioenergetics,and apoptosis.Importantly,emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer’s disease,amyotrophic lateral sclerosis,and Parkinson’s disease.This review will focus on the architecture and function of MAMs and its involvement in the neurodegenerative diseases.展开更多
Nonalcoholic fatty liver disease(NAFLD)encompasses a spectrum of pathologies,ranging from steatosis to nonalcoholic steatohepatitis(NASH).The factors promoting the progression of steatosis to NASH are still unclear.Re...Nonalcoholic fatty liver disease(NAFLD)encompasses a spectrum of pathologies,ranging from steatosis to nonalcoholic steatohepatitis(NASH).The factors promoting the progression of steatosis to NASH are still unclear.Recent studies suggest that mitochondrial lipid composition is critical in NASH develop-ment.Here,we showed that CDP-DAG synthase 2(Cds2)was downregulated in genetic or diet-induced NAFLD mouse models.Liver-specific deficiency of Cds2 provoked hepatic steatosis,inflammation and fibrosis in five-week-old mice.CDS2 is enriched in mitochondria-associated membranes(MAMs),and hepatic Cds2 deficiency impaired mitochondrial function and decreased mitochondrial PE levels.Overexpression of phosphatidylserine decarboxylase(PISD)alleviated the NASH-like phenotype in Cds2^(f/f);AlbCre mice and abnormal mitochondrial morphology and function caused by CDS2 deficiency in hepatocytes.Additionally,dietary supplementation with an agonist of peroxisome proliferator-activated receptor alpha(PPARa)attenuated mitochondrial defects and ameliorated the NASH-like phe-notype in Cds2^(f/f);AlbCre mice.Finally,Cds2 overexpression protected against high-fat diet-induced hepatic steatosis and obesity.Thus,Cds2 modulates mitochondrial function and NASH development.展开更多
Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted d...Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.展开更多
MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochond...MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation(i.e.,miR-142-3p,miR-142-5p,and miR-146a)are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury.In the present study,we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats.In addition,several inflammatory genes were analyzed in the cytosol fractions.The analysis showed that while elevated levels were observed in cytoplasm,the mitochondria-enriched miRNAs,miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury.Although not statistically significant,miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury,and recovered by 7 days.In contrast,miRNAs that are not enriched in mitochondria,including miR-124a,miR-150,miR-19b,miR-155,and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days.The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury.No major alterations were observed in sham operated animals.This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers.These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling.To test this,we utilized a novel peptide-based nanoparticle strategy for in vitro and in viv展开更多
Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair ce...Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell function.ANSD represents up to 15%of individuals with hearing impairments.Through mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic cases.Here,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell lines.We then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other aspects.Results revealed that these variants resulted in impaired dimerization,compromising AIF function.The reduction reaction of AIF variants had proceeded slower than that of AIF-WT.The average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent apoptosis.The average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in controls.However,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells.Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD treatment.Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.展开更多
基金Projects associated with protein homeostasis in the Liu Lab are financially supported by grants from the National Natural Science Foundation of China(31625004,31872653,and 31800210)the Zhejiang Provincial Talent Program(2019R52005)the 111 Project(B14027).
文摘The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance between protein synthesis and degradation,is essential for cell functions during plant growth,development,and stress resistance.Nucleus-encoded chloroplast-and mitochondrion-targeted proteins and ER-resident proteins are imported from the cytosol and undergo modification and maturation within their respective organelles.Protein folding is an error-prone process that is influenced by both developmental signals and environmental cues;a number of mechanisms have evolved to ensure efficient import and proper folding and maturation of proteins in plant organelles.Misfolded or damaged proteins with nonnative conformations are subject to degradation via complementary or competing pathways:intraorganelle proteases,the organelle-associated ubiquitin-proteasome system,and the selective autophagy of partial or entire organelles.When proteins in nonnative conformations accumulate,the organellespecific unfolded protein response operates to restore protein homeostasis by reducing protein folding demand,increasing protein folding capacity,and enhancing components involved in proteasome-associated protein degradation and autophagy.This review summarizes recent progress on the understanding of protein quality control in the ER,chloroplasts,and mitochondria in plants,with a focus on common mechanisms shared by these organelles during protein homeostasis.
基金supported by fund from the National Natural Science Foundation of China(32172322)。
文摘Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability or dysfunction may be the key stimulating factors to activate NLRP3 inflammasome,and sustained Ca^(2+)transfer can result in mitochondrial dysfunction.We focused on KCs to explore the damage to mitochondria by EA.After EA stimulation,cells produced an oxidative stress(OS)response with a significant increase in ROS release.Immunoprecipitation experiments and the addition of inhibitors revealed that the increase in the level of intracellular Ca^(2+)led to Ca^(2+)accumulation in the mitochondrial matrix via mitochondria-associated membranes(MAMs).This was accompanied by a significant release of m ROS,loss of MMP and ATP,and a significant increase in mitochondrial permeability transition pore opening,ultimately leading to mitochondrial instability.These findings confirmed the mechanism that EA induced mitochondrial Ca^(2+)imbalance in KCs via MAM,ultimately leading to mitochondrial dysfunction.Meanwhile,EA induced OS and the decrease of MMP and ATP in rat liver,and significant lesions were found in liver mitochondria.Swelling of the inner mitochondrial cristae and mitochondrial vacuolization occurred,with a marked increase in lipid droplets.
基金Supported by the National Natural Science Foundation of China,No.82204755,and No.81960751the Guangxi Natural Science Foundation Youth Project,No.2023GXNSFBA026274+1 种基金the Guangxi University of Traditional Chinese Medicine School-level Project Youth Fund,No.2022QN008Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine Research Project,No.2022MS008 and No.2022QJ001.
文摘The endoplasmic reticulum(ER)is connected to mitochondria through mitochondria-associated ER membranes(MAMs).MAMs provide a framework for crosstalk between the ER and mitochondria,playing a crucial role in regulating cellular calcium balance,lipid metabolism,and cell death.Dysregulation of MAMs is involved in the development of chronic liver disease(CLD).In CLD,changes in MAMs structure and function occur due to factors such as cellular stress,inflammation,and oxidative stress,leading to abnormal interactions between mitochondria and the ER,resulting in liver cell injury,fibrosis,and impaired liver function.Traditional Chinese medicine has shown some research progress in regulating MAMs signaling and treating CLD.This paper reviews the literature on the association between mitochondria and the ER,as well as the intervention of traditional Chinese medicine in regulating CLD.
基金This work is partly supported by National Institute of Health(grant numbers NS083385 and AG049479 to XZ)Alzheimer’s Association(AARG-16-443584 to XZ).
文摘Endoplasmic reticulum(ER)and mitochondria are tubular organelles with a characteristic“network structure”that facilitates the formation of inter-organellar connections.As a result,mitochondria-associated ER membranes(MAMs),a subdomain of the ER that is tightly linked to and communicates with mitochondria,serve multiple physiological functions including lipid synthesis and exchange,calcium signaling,bioenergetics,and apoptosis.Importantly,emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer’s disease,amyotrophic lateral sclerosis,and Parkinson’s disease.This review will focus on the architecture and function of MAMs and its involvement in the neurodegenerative diseases.
基金the Ministry of Science and Technology of China(2018YFA0506902,2016YFA0500100,and 2018YFA081104)the National Natural Science Foundation of China(9195420001,31771305,and 31630019)Chinese Academy of Sciences(XDPB17)。
文摘Nonalcoholic fatty liver disease(NAFLD)encompasses a spectrum of pathologies,ranging from steatosis to nonalcoholic steatohepatitis(NASH).The factors promoting the progression of steatosis to NASH are still unclear.Recent studies suggest that mitochondrial lipid composition is critical in NASH develop-ment.Here,we showed that CDP-DAG synthase 2(Cds2)was downregulated in genetic or diet-induced NAFLD mouse models.Liver-specific deficiency of Cds2 provoked hepatic steatosis,inflammation and fibrosis in five-week-old mice.CDS2 is enriched in mitochondria-associated membranes(MAMs),and hepatic Cds2 deficiency impaired mitochondrial function and decreased mitochondrial PE levels.Overexpression of phosphatidylserine decarboxylase(PISD)alleviated the NASH-like phenotype in Cds2^(f/f);AlbCre mice and abnormal mitochondrial morphology and function caused by CDS2 deficiency in hepatocytes.Additionally,dietary supplementation with an agonist of peroxisome proliferator-activated receptor alpha(PPARa)attenuated mitochondrial defects and ameliorated the NASH-like phe-notype in Cds2^(f/f);AlbCre mice.Finally,Cds2 overexpression protected against high-fat diet-induced hepatic steatosis and obesity.Thus,Cds2 modulates mitochondrial function and NASH development.
基金financial support from the National Natural Science Foundation for Distinguished Young Scholars (81625023,China)。
文摘Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.
基金supported by a grant(15-12A)from the Kentucky Spinal Cord and Head Injury Research Trust to JES and WXW。
文摘MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation(i.e.,miR-142-3p,miR-142-5p,and miR-146a)are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury.In the present study,we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats.In addition,several inflammatory genes were analyzed in the cytosol fractions.The analysis showed that while elevated levels were observed in cytoplasm,the mitochondria-enriched miRNAs,miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury.Although not statistically significant,miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury,and recovered by 7 days.In contrast,miRNAs that are not enriched in mitochondria,including miR-124a,miR-150,miR-19b,miR-155,and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days.The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury.No major alterations were observed in sham operated animals.This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers.These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling.To test this,we utilized a novel peptide-based nanoparticle strategy for in vitro and in viv
基金the National Natural Science Foundation of China(Nos.32070584,81830028,31771398,82222016,and 8207040100)the Zhejiang Provincial Natural Science Foundation of China(No.LZ19C060001)the Fundamental Research Funds for the Central Universities(No.2019QNA6001)。
文摘Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell function.ANSD represents up to 15%of individuals with hearing impairments.Through mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic cases.Here,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell lines.We then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other aspects.Results revealed that these variants resulted in impaired dimerization,compromising AIF function.The reduction reaction of AIF variants had proceeded slower than that of AIF-WT.The average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent apoptosis.The average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in controls.However,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells.Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD treatment.Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.
