Cardiolipins(CLs),the mitochondria-specific class of phospholipids,are crucial to energy metabolism,cristae structure,and cell apoptosis.CLs present significant challenges in lipidomics analysis due to their structura...Cardiolipins(CLs),the mitochondria-specific class of phospholipids,are crucial to energy metabolism,cristae structure,and cell apoptosis.CLs present significant challenges in lipidomics analysis due to their structural diversity with up to four fatty acyl side chains.In this study,we developed CLAN(Cardio Lipin ANalysis),a comprehensive computational pipeline designed to improve the accuracy and coverage of cardiolipin identification.CLAN integrates three innovative modules:A cardiolipin identification module that utilizes specific fragmentation rules for precise characterization of CLs and their acyl side chains;a false positives detection module that employs retention time(RT)criteria to reduce false positives;and a prediction module that constructs regression models to identify CLs lacking authentic MS/MS spectra.CLAN achieved better identification accuracy and the highest recall rate for potential CL identification compared to the existing lipid identification tools.Furthermore,we applied CLAN program to an intermittent fasting mouse model,delineating tissue-specific CL alterations across 10 tissues.Every-other-day fasting(EODF)can partially counteract the disruption of the CL atlas across multiple tissues caused by high-fat-high-sugar diet feeding,providing novel insights into mitochondrial lipid metabolism under dietary interventions.Taken together,this work not only advances CL identification methodology but also underscores CLAN's potential in comprehensive analysis of CL atlas in the EODF animal model.CLAN is freely accessible on Git Hub.展开更多
Nonalcoholic fatty liver disease(NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, r...Nonalcoholic fatty liver disease(NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species(ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD.展开更多
Phosphatidylglycerol (PG) an important membrane phospholipid required for the synthesis of diphos-phatidylglycerol (DPG) commonly known as cardiolipin (CL) was identified in the fraction of endo-plasmic reticulum (ER)...Phosphatidylglycerol (PG) an important membrane phospholipid required for the synthesis of diphos-phatidylglycerol (DPG) commonly known as cardiolipin (CL) was identified in the fraction of endo-plasmic reticulum (ER)-derived transport vesicles which had no affinity for Golgi. The vesicles were produced in the presence of Brefeldin A (BFA), the agent known to inhibit ER-Golgi transport, and found to display affinity to mitochondria. The analysis revealed that their cargo was not containing proteins that are transported to Golgi, and that their membrane was free of phosphatidylinositol (PI) and ceramides (Cer). The incubation of PG-containing transport vesicles with mitochondria afforded incorporation of their membrane into the Outer Mito-chondrial Membrane (OMM) and formation of lyso-phosphatidylglycerol (LPG). In turn, upon further incubation with fresh transport active cytosol, the mitochondrial LPG was converted to PG. The results of analysis of the OMM, Inner Mitochondrial Mem-brane (IMM) and Inner Mitochondrial Space Components (IMSC) strongly suggest that PG-containing transport vesicles deliver nuclear DNA translation products to the IMSC and thus facilitate CL synthesis in the IMM. In summary, our studies provide evidence that ER-generated PG-enriched transport vesicles represent the general pathway for restitution of mitochondrial membranes and the delivery of nuclear DNA translation products that generate CL, and thus sustain the mitochondrial matrix CL-dependent metabolic reactions.展开更多
Cardiolipin （CL） is a phospholipid exclusively localized in inner mitochondrial membrane where it is required for oxidative phosphorylation, ATP synthesis, and mitochondrial bioenergetics. The biological functions o...Cardiolipin （CL） is a phospholipid exclusively localized in inner mitochondrial membrane where it is required for oxidative phosphorylation, ATP synthesis, and mitochondrial bioenergetics. The biological functions of CL are thought to depend on its acyl chain composition which is dominated by linoleic acids in metabolically active tissues. This unique feature is not derived from the de novo biosynthesis of CL, rather from a remodeling process that involves in phospholipases and transacylase/acyltransferase. The remodeling process is also believed to be responsible for generation of CL species that causes oxidative stress and mitochondrial dysfunction. CL is highly sensitive to oxidative damages by reactive oxygen species （ROS） due to its high content in polyunsaturated fatty acids and location near the site of ROS production. Consequently, pathological remodeling of CL has been implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, heart failure, neurodegeneration, and aging that are characterized by oxidative stress, CL deficiency, and abnormal CL species. This review summarizes recent progresses in molecular, enzymatic, lipidomic, and metabolic studies that support a critical regulatory role of pathological CL remodeling as a missing link between oxidative stress and mitochondrial dysfunction in metabolic diseases and aging.展开更多
In this study, a lipid membrane was fabricated by fusing cardiolipin-phosphatidylcholine（CL_PC, 1：4） vesicles onto a hydrophobic surface of 1-dodecanethiol（DT） preadsorbed on a nanostructured gold film. By changi...In this study, a lipid membrane was fabricated by fusing cardiolipin-phosphatidylcholine（CL_PC, 1：4） vesicles onto a hydrophobic surface of 1-dodecanethiol（DT） preadsorbed on a nanostructured gold film. By changing the concentration of the DT adsorption solution, we constructed a series of CL PC-DT bilayers with different hydrophobicity to study the effects of lipid membrane characteristics on the adsorption conformation of cytochrome c（Cyt c）. Electrochemical analysis showed that the formal potential is 0.24 V for Cyt c-CL_PC-DT（10）, 0.2 V for Cyt c-CL_PC-DT（20）, and 0.16 V for Cyt c-CL_PC-DT（40） — a gradual positive shift with the decreasing DT concentration — relative to the potential of native cyt c（0.02 V）. Potential-induced surface-enhanced infrared adsorption difference spectroscopy revealed that the gradual positive shift of the formal potential of CL-bound cyt c is determined by the environment with the gradually lowered dielectric constant for the heme cofactor in CL-bound cyt c（Fe^3＋）.展开更多
We report a successful case of a pregnant female positive for anti-cardiolipin antibodies who experienced two abnormal pregnancies with postpartum cerebral hemispheric infarctions. A 38-year-old female diagnosed as be...We report a successful case of a pregnant female positive for anti-cardiolipin antibodies who experienced two abnormal pregnancies with postpartum cerebral hemispheric infarctions. A 38-year-old female diagnosed as being positive for anti-cardiolipin antibodies was referred to our hospital due to her strong desire to have a baby. The administration of Japanese herbal medicine, Sairei-to, as immunosuppressive therapy, and low dose aspirin, as anti-coagulation therapy, were initiated prior to the patient’s pregnancy. Five months after beginning the treatment, the patient conceived spontaneously. At 34 weeks of gestation, emergency cesarean section was performed due to increasing genital bleeding resulting from coincidental placenta previa and the patient delivered an appropriate-for-date female infant (1970 g). Treatment with Japanese herbal medicine (Sairei-to) and low-dose aspirin is considered to be an effective treatment option for patients positive for anti-phospholipid antibodies with past histories of abnormal pregnancies.展开更多
Anti-phospholipid antibodies (APA) like anti-cardiolipin antibodies (ACA) and anti-β2glycoprotien (anti-β2GP) are important cause of venous and arterial thrombosis and other occlusive vascular diseases. The prevalen...Anti-phospholipid antibodies (APA) like anti-cardiolipin antibodies (ACA) and anti-β2glycoprotien (anti-β2GP) are important cause of venous and arterial thrombosis and other occlusive vascular diseases. The prevalence of these antibodies in SLE patients at the time of diagnosis is not known in Indian SLE patients. This study was conducted to evaluate the prevalence of ACA and anti-β2GP autoantibodies in SLE patients and to correlate them with disease activity and immune parameters such as C3, C4 and CRP levels. where 85 SLE patients referred from Rheumatology Department, KEM hospital, Mumbai were studied. SLE disease activity was evaluated by SLE Disease Activity Index (SLEDAI) score at the time of evaluation. All patients studied were in an active stage of disease of which 37.6% patients had renal disorders, which were categorized as Lupus Nephritis (LN) and 62.3% patients did not show any renal manifestations (non-LN). ACA and anti-β2GP autoantibodies, to IgG and IgM subclasses were tested by ELISA. C3, C4 and CRP levels were detected by nephelometer. It was observed that 12.9% patients were IgG-ACA and IgM-ACA positive and ACA positivity was noted more among LN group Anti-β2GP autoantibody positivity was 27.1% for IgG and 31.8% for IgM., IgG-anti-β2GP antibodies were slightly higher in non-LN patients, whereas a higher incidence of IgM-anti-β2GP antibodies were detected in LN patients. Hence detection both ACA and anti-β2GP antibodies along with associated immune parameters were helpful to evaluate their possible association with disease severity in SLE patients. A long term follow up of patients having ACA and anti-β2GP antibodies without thrombotic event is also needed to detect their possible thrombotic event in future along with their clinical presentation.展开更多
Monocyte-derived macrophages(MoMacs)are the most important effector cells that cause pulmonary fibrosis.However,the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the p...Monocyte-derived macrophages(MoMacs)are the most important effector cells that cause pulmonary fibrosis.However,the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear.Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs,identified as Spp1hiMacs,which remain in an immature transitional state of differentiation during silicosis.This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2(Lp-PLA2,encoded by Pla2g7)–acyl-CoA:lysocardiolipin acyltransferase-1(ALCAT1)–cardiolipin(CL)signaling pathway,which interferes with Spp1hiMac differentiation.We demonstrated that in SiO_(2)-induced MoMacs,Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1,resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects.Simultaneously,lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm,which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways.Furthermore,we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model.Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.展开更多
Background Obesity is a risk factor for developing cardiometabolic disease.Exercise training is pivotal in the treatment of obesity and is associated with reduced cardiovascular mortality.This study examined the effec...Background Obesity is a risk factor for developing cardiometabolic disease.Exercise training is pivotal in the treatment of obesity and is associated with reduced cardiovascular mortality.This study examined the effect of high-fat feeding on cardiac morphology and mitochondrial function,alongside the mitigating effects of voluntary exercise training.Methods Six-week-old male C57Bl/6 J mice commenced a high fat diet(HFD)or chow diet and were randomized to receive locked(sedentary)or unlocked(voluntary exercise training(VET))running wheels at 10 weeks of age.Mice were monitored until 30 weeks of age and euthanized for collection of tissues.Magnetic resonance imaging was performed to assess body composition,and echocardiography was performed to assess cardiac function.Results Compared with chow-fed animals,the HFD increased body weight and adiposity and decreased cardiolipins(CL)in the heart,which are required for maintaining adequate mitochondrial respiration.Importantly,VET reversed these effects and induced physiological cardiac hypertrophy.Cardiac mitochondrial respiratory chain analysis revealed decreased complexes II and IV activity following high fat feeding,while VET enhanced complex I activity,emphasizing the cardioprotective effect of exercise training in obesity.Conclusion This study uncovers mechanisms by which obesity and exercise impact cardiac mitochondrial health and suggests the mitochondria is a therapeutic target in obesity-related cardiovascular diseases.展开更多
Cholesterol is an important component of biological membranes. It has specific role in membrane structure and function, such as regulating the membrane fluidity and changing in membrane permeability. Apparently very l...Cholesterol is an important component of biological membranes. It has specific role in membrane structure and function, such as regulating the membrane fluidity and changing in membrane permeability. Apparently very little work has been done on the effect of cholesterol on the polymorphism of cardiolipin (DPG). Recently,展开更多
Cardiolipin （CL）, a lipid specific to mitochondrial inner membrane, presents in this membrane in the range of 20—25% of its total lipids. CL is a lipid with negative charges, rich in unsaturated fatty acyl chains, ...Cardiolipin （CL）, a lipid specific to mitochondrial inner membrane, presents in this membrane in the range of 20—25% of its total lipids. CL is a lipid with negative charges, rich in unsaturated fatty acyl chains, and can undergo non-bilayer phase transition, such as hexagonal (H<sub>11</sub>) phase under certain conditions. It has been reported that the activity for respiratory chain components, cytochrome c oxidase for example, and展开更多
Cardiolipin (CL) with two negative charges and four unsaturated fatty acyl chains is a phosphalipid specific to mitochondrial inner membrane. With the static interaction cytochrome c can be bound to CL. Because of the...Cardiolipin (CL) with two negative charges and four unsaturated fatty acyl chains is a phosphalipid specific to mitochondrial inner membrane. With the static interaction cytochrome c can be bound to CL. Because of the activity of cytochrome c oxidase, CL is required to be tightly bound to this enzyme. However, the effect of CL on the展开更多
Besides providing energy to sustain life,mitochondria also play crucial roles in stress response and programmed cell death.The mitochondrial hallmark lipid,cardiolipin(CL),is essential to the maintenance of mitochondr...Besides providing energy to sustain life,mitochondria also play crucial roles in stress response and programmed cell death.The mitochondrial hallmark lipid,cardiolipin(CL),is essential to the maintenance of mitochondrial structure and function.However,how mitochondria and CL are involved in stress response is not as well defined in plants as in animal and yeast cells.We previously revealed a role for CL in mitochondrial fission and in heat stress response in Arabidopsis.To further determine the involvement of mitochondria and CL in plant heat response,here we treated Arabidopsis seedlings with varied lengths of acute heat stress.These treatments resulted in decreases in mitochondrial membrane potential,disruption of mitochondrial ultrastructure,accumulation of mitochondrial reactive-oxygen species(ROS),and redistribution of CL to the outer mitochondrial membrane and to a novel type of vesicle.The level of the observed changes correlated with the severeness of the heat stress,indicating the strong relevance of these processes to stress response.Our findings provide the basis for studying mechanisms underpinning the role of mitochondria and CL in plant stress response.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
基金supported by grants from the National Key Research and Development Program of China(No.2022YFE0205800)the National Natural Science Foundation of China(No.21974114)+5 种基金Major Science and Technology Special Project of Fujian Province(No.2022YZ036012)the Fundamental Research Funds for the Central Universities(No.20720220003)Project“111”sponsored by the State Bureau of Foreign Experts and Ministry of Education of China(No.BP0618017)to S.-H.LinNatural Science Foundation of Fujian Province of China(No.2022J01330)Natural Science Foundation of Xiamen City of China(No.3502Z20227208)the China Scholarship Council(No.202308350047)to J.Zeng。
文摘Cardiolipins(CLs),the mitochondria-specific class of phospholipids,are crucial to energy metabolism,cristae structure,and cell apoptosis.CLs present significant challenges in lipidomics analysis due to their structural diversity with up to four fatty acyl side chains.In this study,we developed CLAN(Cardio Lipin ANalysis),a comprehensive computational pipeline designed to improve the accuracy and coverage of cardiolipin identification.CLAN integrates three innovative modules:A cardiolipin identification module that utilizes specific fragmentation rules for precise characterization of CLs and their acyl side chains;a false positives detection module that employs retention time(RT)criteria to reduce false positives;and a prediction module that constructs regression models to identify CLs lacking authentic MS/MS spectra.CLAN achieved better identification accuracy and the highest recall rate for potential CL identification compared to the existing lipid identification tools.Furthermore,we applied CLAN program to an intermittent fasting mouse model,delineating tissue-specific CL alterations across 10 tissues.Every-other-day fasting(EODF)can partially counteract the disruption of the CL atlas across multiple tissues caused by high-fat-high-sugar diet feeding,providing novel insights into mitochondrial lipid metabolism under dietary interventions.Taken together,this work not only advances CL identification methodology but also underscores CLAN's potential in comprehensive analysis of CL atlas in the EODF animal model.CLAN is freely accessible on Git Hub.
文摘Nonalcoholic fatty liver disease(NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species(ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD.
文摘Phosphatidylglycerol (PG) an important membrane phospholipid required for the synthesis of diphos-phatidylglycerol (DPG) commonly known as cardiolipin (CL) was identified in the fraction of endo-plasmic reticulum (ER)-derived transport vesicles which had no affinity for Golgi. The vesicles were produced in the presence of Brefeldin A (BFA), the agent known to inhibit ER-Golgi transport, and found to display affinity to mitochondria. The analysis revealed that their cargo was not containing proteins that are transported to Golgi, and that their membrane was free of phosphatidylinositol (PI) and ceramides (Cer). The incubation of PG-containing transport vesicles with mitochondria afforded incorporation of their membrane into the Outer Mito-chondrial Membrane (OMM) and formation of lyso-phosphatidylglycerol (LPG). In turn, upon further incubation with fresh transport active cytosol, the mitochondrial LPG was converted to PG. The results of analysis of the OMM, Inner Mitochondrial Mem-brane (IMM) and Inner Mitochondrial Space Components (IMSC) strongly suggest that PG-containing transport vesicles deliver nuclear DNA translation products to the IMSC and thus facilitate CL synthesis in the IMM. In summary, our studies provide evidence that ER-generated PG-enriched transport vesicles represent the general pathway for restitution of mitochondrial membranes and the delivery of nuclear DNA translation products that generate CL, and thus sustain the mitochondrial matrix CL-dependent metabolic reactions.
基金supported in part by grants NIH(DK076685,Y.S.)Pennsylvania Department of Health using Tobacco Settlement Funds(10-K-273,Y.S.)
文摘Cardiolipin （CL） is a phospholipid exclusively localized in inner mitochondrial membrane where it is required for oxidative phosphorylation, ATP synthesis, and mitochondrial bioenergetics. The biological functions of CL are thought to depend on its acyl chain composition which is dominated by linoleic acids in metabolically active tissues. This unique feature is not derived from the de novo biosynthesis of CL, rather from a remodeling process that involves in phospholipases and transacylase/acyltransferase. The remodeling process is also believed to be responsible for generation of CL species that causes oxidative stress and mitochondrial dysfunction. CL is highly sensitive to oxidative damages by reactive oxygen species （ROS） due to its high content in polyunsaturated fatty acids and location near the site of ROS production. Consequently, pathological remodeling of CL has been implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, heart failure, neurodegeneration, and aging that are characterized by oxidative stress, CL deficiency, and abnormal CL species. This review summarizes recent progresses in molecular, enzymatic, lipidomic, and metabolic studies that support a critical regulatory role of pathological CL remodeling as a missing link between oxidative stress and mitochondrial dysfunction in metabolic diseases and aging.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.9122711421322510+4 种基金and 21105097)the China Postdoctoral Science Foundation(Grant No.2013M530998)the Natural Science Foundation of Jilin ProvinceChina(Grant No.201215092)the President Funds of the Chinese Academy of Sciences
文摘In this study, a lipid membrane was fabricated by fusing cardiolipin-phosphatidylcholine（CL_PC, 1：4） vesicles onto a hydrophobic surface of 1-dodecanethiol（DT） preadsorbed on a nanostructured gold film. By changing the concentration of the DT adsorption solution, we constructed a series of CL PC-DT bilayers with different hydrophobicity to study the effects of lipid membrane characteristics on the adsorption conformation of cytochrome c（Cyt c）. Electrochemical analysis showed that the formal potential is 0.24 V for Cyt c-CL_PC-DT（10）, 0.2 V for Cyt c-CL_PC-DT（20）, and 0.16 V for Cyt c-CL_PC-DT（40） — a gradual positive shift with the decreasing DT concentration — relative to the potential of native cyt c（0.02 V）. Potential-induced surface-enhanced infrared adsorption difference spectroscopy revealed that the gradual positive shift of the formal potential of CL-bound cyt c is determined by the environment with the gradually lowered dielectric constant for the heme cofactor in CL-bound cyt c（Fe^3＋）.
文摘We report a successful case of a pregnant female positive for anti-cardiolipin antibodies who experienced two abnormal pregnancies with postpartum cerebral hemispheric infarctions. A 38-year-old female diagnosed as being positive for anti-cardiolipin antibodies was referred to our hospital due to her strong desire to have a baby. The administration of Japanese herbal medicine, Sairei-to, as immunosuppressive therapy, and low dose aspirin, as anti-coagulation therapy, were initiated prior to the patient’s pregnancy. Five months after beginning the treatment, the patient conceived spontaneously. At 34 weeks of gestation, emergency cesarean section was performed due to increasing genital bleeding resulting from coincidental placenta previa and the patient delivered an appropriate-for-date female infant (1970 g). Treatment with Japanese herbal medicine (Sairei-to) and low-dose aspirin is considered to be an effective treatment option for patients positive for anti-phospholipid antibodies with past histories of abnormal pregnancies.
文摘Anti-phospholipid antibodies (APA) like anti-cardiolipin antibodies (ACA) and anti-β2glycoprotien (anti-β2GP) are important cause of venous and arterial thrombosis and other occlusive vascular diseases. The prevalence of these antibodies in SLE patients at the time of diagnosis is not known in Indian SLE patients. This study was conducted to evaluate the prevalence of ACA and anti-β2GP autoantibodies in SLE patients and to correlate them with disease activity and immune parameters such as C3, C4 and CRP levels. where 85 SLE patients referred from Rheumatology Department, KEM hospital, Mumbai were studied. SLE disease activity was evaluated by SLE Disease Activity Index (SLEDAI) score at the time of evaluation. All patients studied were in an active stage of disease of which 37.6% patients had renal disorders, which were categorized as Lupus Nephritis (LN) and 62.3% patients did not show any renal manifestations (non-LN). ACA and anti-β2GP autoantibodies, to IgG and IgM subclasses were tested by ELISA. C3, C4 and CRP levels were detected by nephelometer. It was observed that 12.9% patients were IgG-ACA and IgM-ACA positive and ACA positivity was noted more among LN group Anti-β2GP autoantibody positivity was 27.1% for IgG and 31.8% for IgM., IgG-anti-β2GP antibodies were slightly higher in non-LN patients, whereas a higher incidence of IgM-anti-β2GP antibodies were detected in LN patients. Hence detection both ACA and anti-β2GP antibodies along with associated immune parameters were helpful to evaluate their possible association with disease severity in SLE patients. A long term follow up of patients having ACA and anti-β2GP antibodies without thrombotic event is also needed to detect their possible thrombotic event in future along with their clinical presentation.
基金supported by the National Key Technologies R&D Program of China(No.2021YFC2500700)the National Natural Science Foundation of China(No.82003406)+2 种基金the Natural Science Foundation of Hebei Province(H2022209073)the China Postdoctoral Science Foundation(2023M733985)the CAMS Institute of Respiratory Medicine Grant for Young Scholars(2023-ZF-69).
文摘Monocyte-derived macrophages(MoMacs)are the most important effector cells that cause pulmonary fibrosis.However,the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear.Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs,identified as Spp1hiMacs,which remain in an immature transitional state of differentiation during silicosis.This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2(Lp-PLA2,encoded by Pla2g7)–acyl-CoA:lysocardiolipin acyltransferase-1(ALCAT1)–cardiolipin(CL)signaling pathway,which interferes with Spp1hiMac differentiation.We demonstrated that in SiO_(2)-induced MoMacs,Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1,resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects.Simultaneously,lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm,which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways.Furthermore,we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model.Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.
基金MAF is supported by an NHMRC Investigator Grant(APP1194141)Research in his laboratory was supported by project grants from the NHMRC(APP1042465,APP1041760,and APP1156511).
文摘Background Obesity is a risk factor for developing cardiometabolic disease.Exercise training is pivotal in the treatment of obesity and is associated with reduced cardiovascular mortality.This study examined the effect of high-fat feeding on cardiac morphology and mitochondrial function,alongside the mitigating effects of voluntary exercise training.Methods Six-week-old male C57Bl/6 J mice commenced a high fat diet(HFD)or chow diet and were randomized to receive locked(sedentary)or unlocked(voluntary exercise training(VET))running wheels at 10 weeks of age.Mice were monitored until 30 weeks of age and euthanized for collection of tissues.Magnetic resonance imaging was performed to assess body composition,and echocardiography was performed to assess cardiac function.Results Compared with chow-fed animals,the HFD increased body weight and adiposity and decreased cardiolipins(CL)in the heart,which are required for maintaining adequate mitochondrial respiration.Importantly,VET reversed these effects and induced physiological cardiac hypertrophy.Cardiac mitochondrial respiratory chain analysis revealed decreased complexes II and IV activity following high fat feeding,while VET enhanced complex I activity,emphasizing the cardioprotective effect of exercise training in obesity.Conclusion This study uncovers mechanisms by which obesity and exercise impact cardiac mitochondrial health and suggests the mitochondria is a therapeutic target in obesity-related cardiovascular diseases.
基金Project supported by the National Natural Science Foundation of China.
文摘Cholesterol is an important component of biological membranes. It has specific role in membrane structure and function, such as regulating the membrane fluidity and changing in membrane permeability. Apparently very little work has been done on the effect of cholesterol on the polymorphism of cardiolipin (DPG). Recently,
基金Project supported by the National Natural Science Foundation of China.
文摘Cardiolipin （CL）, a lipid specific to mitochondrial inner membrane, presents in this membrane in the range of 20—25% of its total lipids. CL is a lipid with negative charges, rich in unsaturated fatty acyl chains, and can undergo non-bilayer phase transition, such as hexagonal (H<sub>11</sub>) phase under certain conditions. It has been reported that the activity for respiratory chain components, cytochrome c oxidase for example, and
基金Project supported by the National Natural Science Foundation of China
文摘Cardiolipin (CL) with two negative charges and four unsaturated fatty acyl chains is a phosphalipid specific to mitochondrial inner membrane. With the static interaction cytochrome c can be bound to CL. Because of the activity of cytochrome c oxidase, CL is required to be tightly bound to this enzyme. However, the effect of CL on the
基金supported by the National Natural Science Foundation of China(32200231)the Zhejiang Provincial Natural Science Foundation of China(LZ23C020002)+1 种基金the National Key Research and Development Program(2022YFD1401600)to RPthe National Science Foundation(MCB 2148206)to JH.
文摘Besides providing energy to sustain life,mitochondria also play crucial roles in stress response and programmed cell death.The mitochondrial hallmark lipid,cardiolipin(CL),is essential to the maintenance of mitochondrial structure and function.However,how mitochondria and CL are involved in stress response is not as well defined in plants as in animal and yeast cells.We previously revealed a role for CL in mitochondrial fission and in heat stress response in Arabidopsis.To further determine the involvement of mitochondria and CL in plant heat response,here we treated Arabidopsis seedlings with varied lengths of acute heat stress.These treatments resulted in decreases in mitochondrial membrane potential,disruption of mitochondrial ultrastructure,accumulation of mitochondrial reactive-oxygen species(ROS),and redistribution of CL to the outer mitochondrial membrane and to a novel type of vesicle.The level of the observed changes correlated with the severeness of the heat stress,indicating the strong relevance of these processes to stress response.Our findings provide the basis for studying mechanisms underpinning the role of mitochondria and CL in plant stress response.
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.
