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1.
Neuroscience Bulletin ; (6): 182-200, 2024.
Article in English | WPRIM | ID: wpr-1010654

ABSTRACT

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.


Subject(s)
Humans , Mice , Animals , Transcranial Magnetic Stimulation , Alzheimer Disease/therapy , Cognitive Dysfunction/therapy , Cognition , Sulfur , Iron , Iron-Sulfur Proteins , Mitochondrial Proteins
2.
Chinese Medical Journal ; (24): 190-199, 2024.
Article in English | WPRIM | ID: wpr-1007747

ABSTRACT

BACKGROUND@#Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown.@*METHODS@#In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF.@*RESULTS@#We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders.@*CONCLUSION@#We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.


Subject(s)
Animals , Humans , Mice , Acute-On-Chronic Liver Failure/pathology , ATP-Dependent Proteases/metabolism , Gluconeogenesis , Hepatocytes/pathology , Liver/metabolism , Mitochondrial Proteins/metabolism , Protease La/metabolism
3.
Chinese Journal of Contemporary Pediatrics ; (12): 726-731, 2023.
Article in Chinese | WPRIM | ID: wpr-982019

ABSTRACT

OBJECTIVES@#To study the genetic characteristics, clinical characteristics, and prognosis of children with primary dilated cardiomyopathy (DCM).@*METHODS@#A retrospective analysis was performed on the medical data of 44 children who were diagnosed with DCM in Hebei Children's Hospital from July 2018 to February 2023. According to the genetic testing results, they were divided into two groups: gene mutation-positive group (n=17) and gene mutation-negative group (n=27). The two groups were compared in terms of clinical data at initial diagnosis and follow-up data.@*RESULTS@#Among the 44 children with DCM, there were 21 boys (48%) and 23 girls (52%). Respiratory symptoms including cough and shortness of breath were the most common symptom at initial diagnosis (34%, 15/44). The detection rate of gene mutations was 39% (17/44). There were no significant differences between the two groups in clinical characteristics, proportion of children with cardiac function grade Ⅲ or Ⅳ, brain natriuretic peptide levels, left ventricular ejection fraction, and left ventricular fractional shortening at initial diagnosis (P>0.05). The median follow-up time was 23 months, and 9 children (20%) died, including 8 children from the gene mutation-positive group, among whom 3 had TTN gene mutation, 2 had LMNA gene mutation, 2 had TAZ gene mutation, and 1 had ATAD3A gene mutation. The gene mutation-positive group had a significantly higher mortality rate than the gene mutation-negative group (P<0.05).@*CONCLUSIONS@#There is no correlation between the severity of DCM at initial diagnosis and gene mutations in children. However, children with gene mutations may have a poorer prognosis.


Subject(s)
Male , Female , Humans , Child , Stroke Volume , Retrospective Studies , Ventricular Function, Left , Phenotype , Cardiomyopathy, Dilated/diagnosis , Mutation , ATPases Associated with Diverse Cellular Activities/genetics , Membrane Proteins/genetics , Mitochondrial Proteins/genetics
4.
Chinese Journal of Cellular and Molecular Immunology ; (12): 318-324, 2023.
Article in Chinese | WPRIM | ID: wpr-981871

ABSTRACT

Objective To study the effect and mechanism of blueberry on regulating the mitochondrial inner membrane protein mitofilin/Mic60 in an in vitro model of metabolic dysfunction-associated liver disease (MAFLD). Methods L02 human hepatocytes were induced by free fatty acids (FFA) to establish MAFLD cell model. A normal group, a model group, an 80 μg/mL blueberry treatment group, a Mic60 short hairpin RNA (Mic60 shRNA) transfection group, and Mic60 knockdown combined with an 80 μg/mL blueberry treatment group were established. The intracellular lipid deposition was observed by oil red O staining, and the effect of different concentrations of blueberry pulp on the survival rate of L02 cells treated with FFA was measured by MTT assay. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) contents were measured by visible spectrophotometry. The expression of reactive oxygen species (ROS) in hepatocytes was observed by fluorescence microscopy, and the mRNA and protein expression of Mic60 were detected by real-time quantitative PCR and Western blot analysis, respectively. Results After 24 hours of FFA stimulation, a large number of red lipid droplets in the cytoplasm of L02 cells was observed, and the survival rate of L02 cells treated with 80 μg/mL blueberry was higher. The results of ALT, AST, TG, TC, MDA and the fluorescence intensity of ROS in blueberry treated group were lower than those in model group, while the levels of SOD, GSH, Mic60 mRNA and protein in blueberry treated group were higher than those in model group. Conclusion Blueberry promotes the expression of Mic60, increases the levels of SOD and GSH in hepatocytes, and reduces the production of ROS, thus alleviating the injury of MAFLD hepatocytes and regulating the disorder of lipid metabolism.


Subject(s)
Humans , Blueberry Plants/chemistry , Hepatocytes/metabolism , Liver/metabolism , Liver Diseases/metabolism , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism , Superoxides/metabolism , Mitochondrial Membranes/metabolism , Mitochondrial Proteins/metabolism , Plant Extracts/pharmacology
5.
Acta Physiologica Sinica ; (6): 160-170, 2023.
Article in Chinese | WPRIM | ID: wpr-980993

ABSTRACT

This study aimed to investigate the effect of treadmill exercise on neuropathic pain and to determine whether mitophagy of the anterior cingulate cortex (ACC) contributes to exercise-mediated amelioration of neuropathic pain. Chronic constriction injury of the sciatic nerve (CCI) was used to establish a neuropathic pain model in Sprague-Dawley (SD) rats. Von-Frey filaments were used to assess the mechanical paw withdrawal threshold (PWT), and a thermal radiation meter was used to assess the thermal paw withdrawal latency (PWL) in rats. qPCR was used to evaluate the mRNA levels of Pink1, Parkin, Fundc1, and Bnip3. Western blot was used to evaluate the protein levels of PINK1 and PARKIN. To determine the impact of the mitophagy inducer carbonyl cyanide m-chlorophenylhydrazone (CCCP) on pain behaviors in CCI rats, 24 SD rats were randomly divided into CCI drug control group (CCI+Veh group), CCI+CCCP low-dose group (CCI+CCCP0.25), CCI+CCCP medium-dose group (CCI+CCCP2.5), and CCI+CCCP high-dose group (CCI+CCCP5). Pain behaviors were assessed on 0, 1, 3, 5, and 7 days after modeling. To explore whether exercise regulates pain through mitophagy, 24 SD rats were divided into sham, CCI, and CCI+Exercise (CCI+Exe) groups. The rats in the CCI+Exe group underwent 4-week low-moderate treadmill training one week after modeling. The mechanical pain and thermal pain behaviors of the rats in each group were assessed on 0, 7, 14, 21, and 35 days after modeling. Western blot was used to detect the levels of the mitophagy-related proteins PINK1, PARKIN, LC3 II/LC3 I, and P62 in ACC tissues. Transmission electron microscopy was used to observe the ultrastructure of mitochondrial morphology in the ACC. The results showed that: (1) Compared with the sham group, the pain thresholds of the ipsilateral side of the CCI group decreased significantly (P < 0.001). Meanwhile, the mRNA and protein levels of Pink1 were significantly higher, and those of Parkin were lower in the CCI group (P < 0.05). (2) Compared with the CCI+Veh group, each CCCP-dose group showed higher mechanical and thermal pain thresholds, and the levels of PINK1 and LC3 II/LC3 I were elevated significantly (P < 0.05, P < 0.01). (3) The pain thresholds of the CCI+Exe group increased significantly compared with those of the CCI group after treadmill intervention (P < 0.001, P < 0.01). Compared with the CCI group, the protein levels of PINK1 and P62 were decreased (P < 0.001, P < 0.01), and the protein levels of PARKIN and LC3 II/LC3 I were increased in the CCI+Exe group (P < 0.01, P < 0.05). Rod-shaped mitochondria were observed in the ACC of CCI+Exe group, and there were little mitochondrial fragmentation, swelling, or vacuoles. The results suggest that the mitochondrial PINK1/PARKIN autophagy pathway is blocked in the ACC of neuropathic pain model rats. Treadmill exercise could restore mitochondrial homeostasis and relieve neuropathic pain via the PINK1/PARKIN pathway.


Subject(s)
Rats , Animals , Mitophagy/physiology , Rats, Sprague-Dawley , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Gyrus Cinguli , Neuralgia , Ubiquitin-Protein Ligases/metabolism , Protein Kinases , Membrane Proteins/metabolism , Mitochondrial Proteins/metabolism
6.
Chinese journal of integrative medicine ; (12): 170-178, 2023.
Article in English | WPRIM | ID: wpr-971338

ABSTRACT

OBJECTIVE@#To explore the protective effect and possible mechanisms of bloodletting acupuncture at Jing-well points (BAJP) pre-treatment on acute hypobaric hypoxia (AHH)-induced myocardium injury rat.@*METHODS@#Seventy-five rats were randomly divided into 5 groups by a random number table: a control group (n=15), a model group (n=15), a BAJP group (n=15), a BAJP+3-methyladenine (3-MA) group (n=15), and a BANA (bloodletting at nonacupoint; tail bleeding, n=15) group. Except for the control group, the AHH rat model was established in the other groups, and the corresponding treatment methods were adopted. Enzyme-linked immunosorbent assay (ELISA) was used to detect creatine kinase isoenzyme MB (CK-MB) and cardiac troponins I (CTnI) levels in serum and superoxide dismutase (SOD) and malondialdehyde (MDA) levels in myocardial tissue. Hematoxylin-eosin (HE) staining was used to observe myocardial injury, and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was used to observe cell apoptosis. Transmission electron microscopy detection was used to observe mitochondrial damage and autophagosomes in the myocardium. The mitochondrial membrane potential of the myocardium was analyzed with the fluorescent dye JC-1. Mitochondrial respiratory chain complex (complex I, III, and IV) activities and ATPase in the myocardium were detected by mitochondrial respiratory chain complex assay kits. Western blot analysis was used to detect the autophagy index and hypoxia inducible factor-1α (HIF-1α)/Bcl-2 and adenovirus E1B 19k Da-interacting protein 3 (BNIP3) signaling.@*RESULTS@#BAJP reduced myocardial injury and inhibited myocardial cell apoptosis in AHH rats. BAJP pretreatment decreased MDA levels and increased SOD levels in AHH rats (all P<0.01). Moreover, BAJP pretreatment increased the mitochondrial membrane potential (P<0.01), mitochondrial respiratory chain complex (complexes I, III, and IV) activities (P<0.01), and mitochondrial ATPase activity in AHH rats (P<0.05). The results from electron microscopy demonstrated that BAJP pretreatment improved mitochondrial swelling and increased the autophagosome number in the myocardium of AHH rats. In addition, BAJP pretreatment activated the HIF-1α/BNIP3 pathway and autophagy. Finally, the results of using 3-MA to inhibit autophagy in BAJP-treated AHH rats showed that suppression of autophagy attenuated the treatment effects of BAJP in AHH rats, further proving that autophagy constitutes a potential target for BAJP treatment of AHH.@*CONCLUSION@#BAJP is an effective treatment for AHH-induced myocardial injury, and the mechanism might involve increasing HIF-1α/BNIP3 signaling-mediated autophagy and decreasing oxidative stress.


Subject(s)
Animals , Rats , Acupuncture Therapy , Altitude , Apoptosis , Autophagy , Bloodletting , Hypoxia/metabolism , Membrane Proteins/pharmacology , Mitochondrial Proteins/pharmacology , Oxidative Stress , Rats, Sprague-Dawley
7.
Journal of Zhejiang University. Medical sciences ; (6): 738-743, 2023.
Article in English | WPRIM | ID: wpr-1009942

ABSTRACT

An 11-day-old female neonate was admitted for cough with mouth foaming and feeding difficulties. The laboratory results indicated hyperlactatemia, elevated markers of myocardial injury and inflammation, and high levels of acylcarnitine octanoylcarnitine and decanoylcarnitine in tandem mass spectrometry. Ultrasonography and MRI suggested cardiac insufficiency and hypertrophic cardiomyopathy. Whole exome sequencing showed that both the proband and her elderly sister had a compound heterozygous variant of c.1492dup (p.T498Nfs*13) and c.1376T>C (p.F459S) in the ATAD3A gene, inherited from their father and mother, respectively. The diagnosis of Harel-Yoon syndrome was confirmed. The proband and her sister were born with clinical manifestations of metabolic acidosis, hyperlactatemia, feeding difficulties, elevated markers of myocardial injury as well as cardiac insufficiency, and both died in early infancy.


Subject(s)
Humans , Infant, Newborn , Female , Aged , Mutation , Hyperlactatemia , ATPases Associated with Diverse Cellular Activities/chemistry , Membrane Proteins/genetics , Mitochondrial Proteins/genetics
8.
China Journal of Chinese Materia Medica ; (24): 4156-4163, 2023.
Article in Chinese | WPRIM | ID: wpr-1008612

ABSTRACT

This study explored the effects of Buyang Huanwu Decoction(BYHWD) on platelet activation and differential gene expression after acute myocardial infarction(AMI). SD rats were randomly divided into a sham-operated group, a model group, a positive drug(aspirin) group, and a BYHWD group. Pre-treatment was conducted for 14 days with a daily oral dose of 1.6 g·kg~(-1) BYHWD and 0.1 g·kg~(-1) aspirin. The AMI model was established using the high ligation of the left anterior descending coronary artery method. The detection indicators included myocardial infarct size, heart function, myocardial tissue pathology, peripheral blood flow perfusion, platelet aggregation rate, platelet membrane glycoprotein CD62p expression, platelet transcriptomics, and differential gene expression. The results showed that compared with the sham-operated group, the model group showed reduced ejection fraction and cardiac output, decreased peripheral blood flow, and increased platelet aggregation rate and CD62p expression, and activated platelets. At the same time, TXB_2 content increased and 6-keto-PGF1α content decreased in serum. Compared with the model group, BYHWD increased ejection fraction and cardiac output, improved blood circulation in the foot and tail regions and cardiomyocytes arrangement, reduced myocardial infarct size and inflammatory infiltration, down-regulated platelet aggregation rate and CD62p expression, reduced serum TXB_2 content, and increased 6-keto-PGF1α content. Platelet transcriptome sequencing results revealed that BYHWD regulated mTOR-autophagy pathway-related genes in platelets. The differential gene expression levels were detected using real-time quantitative PCR. BYHWD up-regulated mTOR, down-regulated autophagy-related FUNDC1 and PINK genes, and up-regulated p62 gene expression. The results demonstrated that BYHWD could regulate platelet activation, improve blood circulation, and protect ischemic myocardium in AMI rats, and its mechanism is related to the regulation of the mTOR-autophagy pathway in platelets.


Subject(s)
Rats , Animals , Rats, Sprague-Dawley , Drugs, Chinese Herbal/therapeutic use , Myocardial Infarction/genetics , Myocardium/metabolism , Aspirin/therapeutic use , TOR Serine-Threonine Kinases/metabolism , Membrane Proteins/metabolism , Mitochondrial Proteins
9.
Chinese Journal of Industrial Hygiene and Occupational Diseases ; (12): 18-23, 2022.
Article in Chinese | WPRIM | ID: wpr-935735

ABSTRACT

Objective: To study the effects of vibration on the expression of mitochondrial fusion and fission genes and ultrastructure of skeletal muscle in rabbits. Methods: Thirty-two 3.5-month-old New Zealand rabbits were randomly divided into low-intensity group, medium-intensity group, high-intensity group and control group, with 8 rabbits in each group. The rabbits in the experimental group were subjected to hind limb vibration load test for 45 days. The vibration intensity of the high intensity group was 12.26 m/s(2), the medium intensity group was 6.13 m/s(2), and the low intensity group was 3.02 m/s(2) according to the effective value of weighted acceleration[a(hw (4))] for 4 hours of equal energy frequency. The control group was exposed to noise only in the same experimental environment as the medium-intensity group. The noise levels of each group were measured during the vibration load experiment. After the test, the mRNA expression of mitochondrial fusion gene (Mfn1/Mfn2) and fission gene (Fis1, Drp1) by RT-PCR in the skeletal muscles were measured and the ultrastructure of the skeletal muscles were observed in high intensity group. Results: The mRNA expression of mitochondrial in the skeletal muscle tissues of control group, low intensity group, medium intensity group and high intensity group were Mfn1: 3.25±1.36, 3.85±1.90, 4.53±2.31 and 11.63±7.68; Mfn2: 0.68±0.25, 1.02±0.40, 0.94±0.33 and 1.40±0.45; Fis1: 1.05±0.62, 1.15±0.59, 1.53±1.06 and 2.46±1.51 and Drp1: 3.72±1.76, 2.91±1.63, 3.27±2.01 and 4.21±2.46, respectively. Compared with the control group, the expressions of Mfn1 mRNA, Mfn2 mRNA and Fis1 mRNA in the high-intensity group increased significantly (P<0.05) , and the expressions of Mfn2 mRNA in the medium-intensity group and the low-intensity group increased significantly (P<0.05) . Compared with the control group, the ultrastructure of skeletal muscle of high intensity group showed mitochondrial focal accumulation, cristae membrane damage, vacuole-like changes; Z-line irregularity of muscle fibers, and deficiency of sarcomere. Conclusion: Vibration must be lead to the abnormal mitochondrial morphology and structure and the disorder of energy metabolism due to the expression imbalance of mitochondrial fusion and fission genes in skeletal muscles of rabbits, which may be an important target of vibration-induced skeletal muscle injury.


Subject(s)
Animals , Rabbits , Hindlimb/metabolism , Mitochondria/metabolism , Mitochondrial Dynamics , Mitochondrial Proteins/pharmacology , Muscle, Skeletal , Vibration/adverse effects
10.
China Journal of Chinese Materia Medica ; (24): 1897-1903, 2022.
Article in Chinese | WPRIM | ID: wpr-928186

ABSTRACT

Mitochondrion, as the main energy-supply organelle, is the key target region that determines neuronal survival and death during ischemia. When an ischemic stroke occurs, timely removal of damaged mitochondria is very important for improving mitochondrial function and repairing nerve damage. This study investigated the effect of ligustilide(LIG), an active ingredient of Chinese medicine, on mitochondrial function and mitophagy based on the oxygen and glucose deprivation/reperfusion(OGD/R)-induced injury model in HT22 cells. By OGD/R-induced injury model was induced in vitro, HT22 cells were pre-treated with LIG for 3 h, and the cell viability was detected by the CCK-8 assay. Immunofluorescence and flow cytometry were used to detect indicators related to mitochondrial function, such as mitochondrial membrane potential, calcium overload, and reactive oxygen species(ROS). Western blot was used to detect the expression of dynamin-related protein 1(Drp1, mitochondrial fission protein) and cleaved caspase-3(apoptotic protein). Immunofluorescence was used to observe the co-localization of the translocase of outer mitochondrial membrane 20(TOMM20, mitochondrial marker) and lysosome-associated membrane protein 2(LAMP2, autophagy marker). The results showed that LIG increased the cell viability of HT22 cells as compared with the conditions in the model group. Furthermore, LIG also inhibited the ROS release, calcium overload, and the decrease in mitochondrial membrane potential in HT22 cells after OGD/R-induced injury, facilitated Drp1 expression, and promoted the co-localization of TOMM20 and LAMP2. The findings indicate that LIG can improve the mitochondrial function after OGD/R-induced injury and promote mitophagy. When mitophagy inhibitor mdivi-1 was administered, the expression of apoptotic protein increased, suggesting that the neuroprotective effect of LIG may be related to the promotion of mitophagy.


Subject(s)
Humans , 4-Butyrolactone/analogs & derivatives , Apoptosis , Calcium/pharmacology , Glucose/metabolism , Mitochondrial Proteins , Mitophagy , Reactive Oxygen Species/metabolism , Reperfusion Injury/genetics
11.
Acta Physiologica Sinica ; (6): 1025-1034, 2021.
Article in Chinese | WPRIM | ID: wpr-921307

ABSTRACT

Cells selectively scavenge redundant or damaged mitochondria by mitophagy, which is an important mechanism of mitochondrial quality control. Recent studies have shown that mitophagy is mainly regulated by autophagy-related genes (Atgs) in yeast cells, while mitochondrial membrane associated proteins such as PTEN-induced putative kinase 1 (PINK1), NIX/BNIP3L, BNIP3, FUN14 domain containing 1 (FUNDC1), FKBP8/FKBP38, Bcl-2-like protein 13 (Bcl2L13), nucleotide binding domain and leucine-rich-repeat-containing proteins X1 (NLRX1), prohibitin 2 (PHB2) and lipids such as cardiolipin (CL) are the key mitophagic receptors in mammalian cells, which can selectively recognize damaged mitochondria, recruit them into isolation membranes by binding to microtubule-associated protein 1 light chain 3 (LC3) or γ-aminobutyric acid receptor-associated protein (GABARAP), and then fuse with lysosomes to eliminate the trapped mitochondria. This article reviews recent research progress of mitophagy-related receptor proteins.


Subject(s)
Animals , Apoptosis Regulatory Proteins , Autophagy , Microtubule-Associated Proteins , Mitochondria , Mitochondrial Proteins/genetics , Mitophagy , Prohibitins
12.
Acta Physiologica Sinica ; (6): 835-844, 2021.
Article in Chinese | WPRIM | ID: wpr-921287

ABSTRACT

The mitochondrial unfolded protein response is an important component of the mitochondrial protein quality control program. It can effectively remove unfolded or misfolded proteins under stress, and maintain a stable and healthy mitochondrial pool. The mitochondrial unfolded protein response is coordinated by multiple signaling pathways. The classical ATF4/ATF5-CHOP pathway is induced by accumulation of unfolded or misfolded proteins in the mitochondrial matrix, which reduces stress toxicity by regulating molecular chaperones and proteases. Sirt3-FOXO3a-SOD2 pathway, located in the mitochondrial matrix, plays an important role in anti-oxidative damage. The ERα-NRF1-HTRA2 pathway mainly removes unfolded proteins in the mitochondrial membrane space and improves the quality control of mitochondrial proteins. These three signaling pathways work both independently and cooperatively to enhance mitochondrial capacity and maintain health under stress.


Subject(s)
Mitochondria , Mitochondrial Proteins/metabolism , Oxidative Stress , Signal Transduction , Unfolded Protein Response
13.
Journal of Experimental Hematology ; (6): 1019-1027, 2021.
Article in Chinese | WPRIM | ID: wpr-888513

ABSTRACT

OBJECTIVE@#To detect the expression of different transcripts of lactamase β(LACTB) gene in leukemic cell lines.@*METHODS@#NCBI website and DNAstar software were used to detect the Bioinformatics analysis of LACTB. The expression of different transcripts of LACTB gene in leukemic cell lines (THP-1, HL60, K562, U937, Jurkat and Raji) was detected by reverse transcription PCR (RT-PCR), DNA and clone sequencing; the expression of different transcripts of LACTB gene in leukemic cell lines was detected by Quantitative Real-time PCR.@*RESULTS@#There were a variety of splicing isomers in LACTB, and it could produce a variety of protein isomers with conserved N-terminal and different C-terminal, moreover, there were many splice isoforms of LACTB in leukemia cell lines, and there were different expression patterns in different cell lines, including XR1, V1, V2 and V3. The expression of total LACTB showed high in HL60 cells, while low in Raji cells, and the difference was statistically significant (P<0.05). The V1 was high expression in U937 cells but low in Raji cells, and the difference was statistically significant (P<0.05). V2 was high expression in HL60 cells but lowly in Raji cells, and the difference was statistically significant (P<0.05). The expression of V3 was low in THP-1 cells, which was significantly different as compared with that in normal bone marrow (P<0.05).@*CONCLUSION@#The reaserch found that there are many splice isomers of LACTB in leukemic cell lines, and there are different expression patterns in different cell lines.


Subject(s)
Humans , Alternative Splicing , HL-60 Cells , Leukemia/genetics , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , RNA Splicing , U937 Cells , beta-Lactamases/genetics
14.
Acta Physiologica Sinica ; (6): 631-642, 2020.
Article in Chinese | WPRIM | ID: wpr-878208

ABSTRACT

The aim of the present study was to investigate the effects of exercises with different durations and intensities on mitochondrial autophagy and FUNDC1 in rat skeletal muscles. Sixty male Sprague-Dawley rats were randomly divided into 2- and 4-week control groups (Con), moderate-intensity exercise groups (M-ex groups, treadmill exercise, 16 m/min, 1 h/d, 6 d/week), and high-intensity exercise groups (Hi-ex groups, treadmill exercise, 35 m/min, 20 min/d, 6 d/week). The bilateral soleus muscles were separated after the intervention, and paraffin sections were prepared for transmission electron microscopy. ELISA method was used to detect the content of citrate synthase (CS). The co-localizations of microtubule-associated protein 1 light chain 3 (LC3)/cytochrome c oxidase IV (COX-IV), FUNDC1/COX-IV and LC3/FUNDC1 were observed by immunofluorescent staining in frozen sections. The skeletal muscle mitochondria were extracted, and the expression of autophagy-related proteins, including AMPKα, p-AMPKα, Unc-51 like kinase 1 (ULK1), FUNDC1, LC3 and p62, were detected by Western blot. The results showed that exercise increased mitochondrial function, i.e. peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), COX-I protein expression levels and CS content. There was no difference of mitochondrial function parameters between 2-week M-ex and 2-week Hi-ex groups, while mitochondrial function of 4-weeks Hi-ex group was significantly lower than that of 4-week M-ex group. Under the same exercise intensity, mitochondrial autophagy activation in skeletal muscle of 4-week exercise was higher than that in 2-week exercise group; Under the same duration of exercise, mitochondrial autophagy activation of Hi-ex group was higher than that in M-ex group. Both 2- and 4-week exercise intervention increased LC3/COX-IV, COX-IV/FUNDC1, and FUNDC1/LC3 co-localizations. Exercise increased LC3-II/LC3-I ratio, down-regulated p62 protein expression level, up-regulated FUNDC1, ULK1 protein expression levels and AMPKα phosphorylation, and the changes of these proteins in 4-week Hi-ex group were significantly greater than those in 4-week M-ex group. These results suggest exercise induces mitochondrial autophagy in skeletal muscles, and the activity of autophagy is related to the duration and intensity of exercise. The induction mechanism of exercise may involve the mediation of FUNDC1 expression through AMPK-ULK1 pathway.


Subject(s)
Animals , Humans , Male , Rats , Autophagy , Exercise Therapy , Membrane Proteins/physiology , Mitochondria , Mitochondrial Proteins/physiology , Muscle, Skeletal/metabolism , Rats, Sprague-Dawley
15.
Journal of Lipid and Atherosclerosis ; : 92-109, 2020.
Article in English | WPRIM | ID: wpr-786079

ABSTRACT

In type 2 diabetes (T2D), the leading cause of death is cardiovascular complications. One mechanism contributing to cardiac pathogenesis is alterations in metabolism, with the diabetic heart exhibiting increased fatty acid oxidation and reduced glucose utilisation. The processes classically thought to underlie this metabolic shift include the Randle cycle and changes to gene expression. More recently, alternative mechanisms have been proposed, most notably, changes in post-translational modification of mitochondrial proteins in the heart. This increased understanding of how metabolism is altered in the diabetic heart has highlighted new therapeutic targets, with an aim to improve cardiac function in T2D. This review focuses on metabolism in the healthy heart and how this is modified in T2D, providing evidence for the mechanisms underlying this shift. There will be emphasis on the current treatments for the heart in diabetes, alongside efforts for metabocentric pharmacological therapies.


Subject(s)
Cause of Death , Gene Expression , Glucose , Heart , Metabolism , Mitochondrial Proteins , Protein Processing, Post-Translational
16.
Acta Physiologica Sinica ; (6): 249-254, 2020.
Article in Chinese | WPRIM | ID: wpr-827062

ABSTRACT

The aim of this study was to investigate the effect of edaravone (Eda) on the balance of mitochondrial fusion and fission in Parkinson's disease (PD) cell model. A cell model of PD was established by treating PC12 cells with 500 μmol/L 1-methyl-4-phenylpyridinium (MPP). Thiazole blue colorimetry (MTT) was used to detect the effect of different concentrations of Eda on the survival rate of PC12 cells exposed to MPP. The mitochondrial morphology was determined by laser confocal microscope. Western blot was used to measure the protein expression levels of mitochondrial fusion- and fission-related proteins, including OPA1, MFN2, DRP1 and Fis1. The results showed that pretreatment with different concentrations of Eda antagonized MPP-induced PC12 cell damage in a dose-dependent manner. The PC12 cells treated with MPP showed mitochondrial fragmentation, up-regulated DRP1 and Fis1 protein expression levels, and down-regulated MFN2 and OPA1 protein expression levels. Eda could reverse the above changes in the MPP-treated PC12 cells, but did not affect Fis1 protein expression. These results suggest that Eda has a protective effect on the mitochondrial fusion disruption induced by MPP in PC12 cells. The mechanism may be related to the up-regulation of OPA1/MFN2 and down-regulation of DRP1.


Subject(s)
Animals , Rats , 1-Methyl-4-phenylpyridinium , Dynamins , Edaravone , Pharmacology , GTP Phosphohydrolases , Mitochondria , Mitochondrial Dynamics , Mitochondrial Proteins , PC12 Cells , Parkinson Disease , Up-Regulation
17.
Acta Physiologica Sinica ; (6): 475-487, 2020.
Article in Chinese | WPRIM | ID: wpr-827039

ABSTRACT

The abnormality of mitochondrial morphology and function is closely related to the pathogenesis of many diseases. Mitochondrial fusion-fission dynamics are critical to maintain normal morphology, distribution and quantity of mitochondria, and ensure the normal activity of cells. In addition, mitochondrial autophagy (mitophagy) plays an important role in maintaining mitochondrial quality by degrading aging or damaged mitochondria. Many previous studies showed that mitochondrial dynamics and mitophagy can regulate each other to sustain mitochondrial network homeostasis. Clarifying regulatory mechanisms of mitochondrial dynamics and mitophagy is of great significance for revealing the molecular mechanism of various diseases and for the development of new drugs targeting mitochondrial dynamics proteins or mitophagy regulatory proteins. This review focuses on the role of mitochondrial dynamics and mitophagy in mitochondrial quality control, regulatory mechanism, the interplay between those two processes, and their roles in human-related diseases.


Subject(s)
Humans , Autophagy , Mitochondria , Mitochondrial Dynamics , Mitochondrial Proteins , Mitophagy
18.
Journal of Southern Medical University ; (12): 523-527, 2019.
Article in Chinese | WPRIM | ID: wpr-772049

ABSTRACT

OBJECTIVE@#To investigate whether autophagy mediates the effects of aldehyde dehydrogenase 2 (ALDH2) on the proliferation of neonatal rat cardiac fibroblasts cultured in high glucose.@*METHODS@#Cardiac fibroblasts were isolated from neonatal (within 3 days) SD rats and subcultured. The fibroblasts of the third passage, after identification with immunofluorescence staining for vimentin, were treated with 5.5 mmol/L glucose (control group), 30 mmol/L glucose (high glucose group), or 30 mmol/L glucose in the presence of Alda-1 (an ALDH2 agonist), daidzin (an ALDH2 2 inhibitor), or both. Western blotting was employed to detect ALDH2, microtubule-associated protein 1 light chain 3B subunit (LC3B) and Beclin-1 in the cells, and a hydroxyproline detection kit was used for determining hydroxyproline content in cell culture medium; CCK- 8 kit was used for assessing the proliferation ability of the cardiac fibroblasts after the treatments.@*RESULTS@#Compared with the control cells, the cells exposed to high glucose exhibited obviously decreased expressions of ALDH2, Beclin-1 and LC3B and increased cell number and hydroxyproline content in the culture medium. Treatment of the high glucose-exposed cells with Alda-1 significantly increased Beclin-1, LC3B, and ALDH2 protein expressions and lowered the cell number and intracellular hydroxyproline content, whereas the application of daidzin resulted in reverse changes in the expressions of ALDH2, Beclin-1 and LC3B, viable cell number and intracellular hydroxyproline content in high glucose-exposed cells.@*CONCLUSIONS@#Mitochondrial ALDH2 inhibits the proliferation of neonatal rat cardiac fibroblasts induced by high glucose, and the effect is possibly mediated by the up-regulation of autophagy-related proteins Beclin-1 and LC3B.


Subject(s)
Animals , Rats , Aldehyde Dehydrogenase , Aldehyde Dehydrogenase, Mitochondrial , Metabolism , Animals, Newborn , Autophagy , Beclin-1 , Physiology , Fibroblasts , Glucose , Microtubule-Associated Proteins , Mitochondrial Proteins , Rats, Sprague-Dawley
19.
Journal of Lipid and Atherosclerosis ; : 26-47, 2019.
Article in English | WPRIM | ID: wpr-765654

ABSTRACT

Diabetes mellitus increases the risk for the development of heart failure even in the absence of coronary artery disease and hypertension, a cardiac entity termed diabetic cardiomyopathy (DC). Clinically, DC is increasingly recognized and typically characterized by concentric cardiac hypertrophy and diastolic dysfunction, ultimately resulting in heart failure with preserved ejection fraction (HFpEF) and potentially even heart failure with reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie the alterations in myocardial structure and function in DC, many of which show similar alterations in the failing heart. Well investigated and established mechanisms of DC include increased myocardial fibrosis, enhanced apoptosis, oxidative stress, impaired intracellular calcium handling, substrate metabolic alterations, and inflammation, among others. In addition, a number of novel mechanisms that receive increasing attention have been identified in recent years, including autophagy, dysregulation of microRNAs, epigenetic mechanisms, and alterations in mitochondrial protein acetylation, dynamics and quality control. This review aims to provide an overview and update of established underlying mechanisms of DC, as well as a discussion of recently identified and emerging mechanisms that may also contribute to the structural and functional alterations in DC.


Subject(s)
Acetylation , Apoptosis , Autophagy , Calcium , Cardiomegaly , Coronary Artery Disease , Diabetes Mellitus , Diabetic Cardiomyopathies , Epigenomics , Fibrosis , Heart , Heart Failure , Hypertension , Inflammation , MicroRNAs , Mitochondrial Proteins , Oxidative Stress , Quality Control
20.
Acta Physiologica Sinica ; (6): 625-636, 2019.
Article in Chinese | WPRIM | ID: wpr-777148

ABSTRACT

Mitochondrial dynamics, involving mitochondrial fusion, fission and autophagy, plays an important role in maintaining cellular physiological function and homeostasis. Mitochondria are the "energy plant" of human body, so the changes of mitochondrial fusion, division and autophagy are important for cell respiration and energy production. On the other hand, energy metabolism influences mitochondrial dynamics in turn. This paper reviewed the recent advances in studies on the relationship between energy metabolism and the proteins regulating mitochondrial fusion, fission and autophagy. The association of mitochondrial dynamics with electron chain complex expression, oxidative phosphorylation and ATP synthesis upon exercise intervention will provide theoretical references for the further studies in sports training and disease intervention.


Subject(s)
Humans , Adenosine Triphosphate , Autophagy , Energy Metabolism , Exercise , Mitochondria , Physiology , Mitochondrial Dynamics , Mitochondrial Proteins , Metabolism
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