OBJECTIVE: To review the research progress of mitochondrial dynamics mediated by optic atrophy 1 (OPA1) in skeletal system diseases. METHODS: The literatures about OPA1-mediated mitochondrial dynamics in recent years were reviewed, and the bioactive ingredients and drugs for the treatment of skeletal system diseases were summarized, which provided a new idea for the treatment of osteoarthritis. RESULTS: OPA1 is a key factor involved in mitochondrial dynamics and energetics and in maintaining the stability of the mitochondrial genome. Accumulating evidence indicates that OPA1-mediated mitochondrial dynamics plays an important role in the regulation of skeletal system diseases such as osteoarthritis, osteoporosis, and osteosarcoma. CONCLUSION OPA1-mediated mitochondrial dynamics provides an important theoretical basis for the prevention and treatment of skeletal system diseases.
Humans ; GTP Phosphohydrolases/genetics* ; Mitochondrial Dynamics ; Osteoarthritis ; Osteoporosis

OBJECTIVE: To investigate the coexisting mutations and clinical significance of Homo sapiens neuroblastoma RAS viral oncogene homolog (NRAS) gene in acute myeloid leukemia (AML) patients. METHODS: High-throughput DNA sequencing and Sanger sequencing were used to detect 51 gene mutations. The occurrence, clinical characteristics and treatment efficacy of coexisting genes with NRAS were investigated. RESULTS: A total of 57 NRAS mutations (17.5%) were detected in 326 patients with AML. Compared with the patients in NRAS non-mutation group, patients in the mutant group were younger (P=0.018) and showed lower platelet count (P=0.033), but there was no significant difference in peripheral leukocyte count, hemoglobin, and sex. For FAB classification, NRAS mutation and M2 subtype showed mutually exclusive (P=0.038). Among 57 patients carried with NRAS mutation, 51 (89.5%) patients carried with other gene mutations, 25 (43.9%) carried with double gene mutations, 10 (17.5%) carried with 3 gene mutations, and 16 (28.1%) corried with ≥ 4 gene mutations. The most common coexisting gene mutation was KRAS (24.6%, 14/57), followed by FLT3-ITD (14.0%, 8/57), RUNX1 (12.3%, 7/57), NPM1 (10.5%, 6/57), PTPN11 (10.5%, 6/57), DNMT3A (10.5%, 6/57) and so on. The age (P=0.013, P=0.005) and peripheral platelet count (P=0.007, P=0.021) of patients with NPM1 or DNMT3A mutations were higher than those of the patients with wild type, but there was no significant difference in peripheral leukocyte count and hemoglobin. Also, there was no significant difference in age, peripheral leukocyte count, hemoglobin, and peripheral platelet count between the patients in KRAS, FLT3-ITD, RUNX1 or PTPN11 mutant group and the wild group. Patients with FLT3-ITD mutations showed a lower complete remission (CR) rate (P=0.044). However, there was no significant difference in CR rate between the patients with KRAS, NPM1, RUNX1, PTPN11 or DNMT3A mutations and the wild group. The CR rate of the patents with single gene mutation, double gene mutations, 3 gene mutations, and≥ 4 gene mutations were decreased gradually, and there was no significant difference in CR rate between pairwise comparisons. CONCLUSION The mutation rate of NRAS mutation is 17.5%, 89.5% of AML patients with NRAS mutation coexist with additional gene mutations. The type of coexisting mutations has a certain impact on clinical characteristics and CR rate of patients with AML.
Core Binding Factor Alpha 2 Subunit/genetics* ; GTP Phosphohydrolases/genetics* ; Humans ; Leukemia, Myeloid, Acute/genetics* ; Membrane Proteins/genetics* ; Mutation ; Nucleophosmin ; Prognosis ; Proto-Oncogene Proteins p21(ras)/genetics* ; fms-Like Tyrosine Kinase 3

This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing.We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.
Adolescent ; Adult ; Aged ; CCAAT-Enhancer-Binding Proteins ; genetics ; Child ; Child, Preschool ; China ; DNA Mutational Analysis ; Female ; GTP Phosphohydrolases ; genetics ; Gene Expression Profiling ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Kaplan-Meier Estimate ; Leukemia, Myeloid, Acute ; genetics ; Male ; Membrane Proteins ; genetics ; Middle Aged ; Mutation ; Nuclear Proteins ; genetics ; Phenotype ; Retrospective Studies ; Young Adult ; fms-Like Tyrosine Kinase 3 ; genetics

To observe the protective effect and mechanism of Sailuotong capsule in focal cerebral ischemia/reperfusion. The 90 min middle cerebral artery occlusion (MCAO) reperfusion model was established. The expressions of dynamin-related protein 1 ( Drp1) and optic atrophy 1 (Opa1) were tested by Western blot. The transmission electron microscope was used to observe the changes in the mitochondrial ultra-structure. The pathological morphological changes were observed through the HE staining. The immunohistochemical method was used to test Drp1 and Opa1 expressions. Sailuotong capsule (33, 16.5 mg x kg(-1), ig) can inhibit the abnormal mitochondrial fission and fusion in the cortical area on the ischemia side and the mitochondrial fission gene expression and promote the mitochondrial fusion gene Opa1 expression, so as to alleviate the energy metabolism disorder caused by ischemia/reperfusion. Sailuotong capsule can inhibit the abnormal mitochondrial dynamics in peri-ischemic regions and maintain the normal morphology of mitochondria, which may be the mechanism of Sailuotong capsule in promoting the self-recovery function in the ischemic brain region.
Animals ; Brain ; drug effects ; metabolism ; Brain Ischemia ; drug therapy ; genetics ; metabolism ; surgery ; Drugs, Chinese Herbal ; administration & dosage ; Dynamins ; genetics ; metabolism ; GTP Phosphohydrolases ; genetics ; metabolism ; Humans ; Male ; Mitochondria ; drug effects ; metabolism ; Rats

Four small GTPase genes which may be relative to sclerotial development were firstly cloned from medicinal fungus Polyporus umbellatus using rapid amplification of cDNA end PCR (RACE) method. The results showed that full-length cDNA of PuRhoA was 698 bp contained 585 bp ORF, which was predicted to encode a 194 amino acid protein with a molecular weight of 21.75 kD with an isoelectric point (pI) of 6.44; the full length cDNA of PuRhoA2 was 837 bp in length and encoded a 194 amino acid protein with a molecular weight of 21.75 kD and an isoelectric point (pI) of 6.33; the full length cDNA of Puypt1 was 896 bp in length and encoded a 204-aa protein with a molecular weight of 22.556 kD and an isoelectric point (pI) of 5.75; the full length cDNA of PuRas was 803 bp in length and encoded a 212-aa protein with a molecular weight of 23.821 kD and an isoelectric point (pI) of 5.2. There are fani acyl transferase enzyme catalytic site and myrcene-transferase enzyme catalytic site in PuRhoA1 while the PuRhoA2 only possess myrcene-transferase enzyme catalytic site. Puypt1 contains the Rab1-Ypt1 conserved domain of small GTPase family and PuRas contains the fani acyl transferase enzyme catalytic site. According to the phylogenetic analysis all these four small GTPase clustered with basidiomycete group. Quantitative real-time PCR analysis revealed that Puypt1, PuRas and PuRhoA1 transcripts were significantly higher in the beginning of sclerotial formation than that in the mycelia, whereas the transcripts levels of PuRhoA2 gene were particularly lower in sclerotia than that in mycelia, suggesting that these four genes might be involved in P umbellatus selerotial development.
Amino Acid Sequence ; Cloning, Molecular ; DNA, Complementary ; Fungal Proteins ; genetics ; GTP Phosphohydrolases ; genetics ; Genes, Fungal ; Mycelium ; Phylogeny ; Polyporus ; enzymology ; genetics ; Real-Time Polymerase Chain Reaction

Thyroid cancer may have small adipose structures detected by microscopy. However, there are no reports of thyroid cancer with gross fat evaluated by radiological methods. We reported a case of a 58-year-old woman with a fat containing thyroid mass. The mass was hyperechoic and ovoid in shape with a smooth margin on ultrasonography. On computed tomography, the mass had markedly low attenuation suggestive of fat, and fine reticular and thick septa-like structures. The patient underwent a right lobectomy. The mass was finally diagnosed as a follicular variant of papillary thyroid cancer with massive stromal fat.
Carcinoma/*diagnosis/pathology/ultrasonography ; Exons ; Female ; GTP Phosphohydrolases/genetics ; Humans ; Immunohistochemistry ; Membrane Proteins/genetics ; Middle Aged ; Mutation ; Thyroid Neoplasms/*diagnosis/pathology/ultrasonography ; Tomography, X-Ray Computed

Animals ; COS Cells ; Cercopithecus aethiops ; Endoplasmic Reticulum ; GTP Phosphohydrolases ; antagonists & inhibitors ; chemistry ; genetics ; metabolism ; GTP-Binding Proteins ; antagonists & inhibitors ; chemistry ; genetics ; metabolism ; Gene Expression ; Genetic Complementation Test ; HeLa Cells ; Humans ; Kinetics ; Membrane Fusion ; genetics ; Membrane Proteins ; antagonists & inhibitors ; chemistry ; genetics ; metabolism ; Protein Multimerization ; RNA, Small Interfering ; genetics ; metabolism ; Recombinant Proteins ; chemistry ; genetics ; metabolism ; Saccharomyces cerevisiae ; genetics ; metabolism ; Saccharomyces cerevisiae Proteins ; genetics ; metabolism ; Vesicular Transport Proteins ; genetics ; metabolism

Formation of the endoplasmic reticulum (ER) network requires homotypic membrane fusion, which involves a class of atlastin (ATL) GTPases. Purified Drosophila ATL is capable of mediating vesicle fusion in vitro, but such activity has not been reported for any other ATLs. Here, we determined the preliminary crystal structure of the cytosolic segment of Drosophila ATL in a GDP-bound state. The structure reveals a GTPase domain dimer with the subsequent three-helix bundles associating with their own GTPase domains and pointing in opposite directions. This conformation is similar to that of human ATL1, to which GDP and high concentrations of inorganic phosphate, but not GDP only, were included. Drosophila ATL restored ER morphology defects in mammalian cells lacking ATLs, and measurements of nucleotide-dependent dimerization and GTPase activity were comparable for Drosophila ATL and human ATL1. However, purified and reconstituted human ATL1 exhibited no in vitro fusion activity. When the cytosolic segment of human ATL1 was connected to the transmembrane (TM) region and C-terminal tail (CT) of Drosophila ATL, the chimera still exhibited no fusion activity, though its GTPase activity was normal. These results suggest that GDP-bound ATLs may adopt multiple conformations and the in vitro fusion activity of ATL cannot be achieved by a simple collection of functional domains.
Animals ; Dimerization ; Drosophila ; Drosophila Proteins ; chemistry ; genetics ; Endoplasmic Reticulum ; chemistry ; GTP Phosphohydrolases ; chemistry ; genetics ; GTP-Binding Proteins ; chemistry ; genetics ; Guanosine Diphosphate ; chemistry ; metabolism ; Humans ; Membrane Proteins ; chemistry ; genetics ; Mutation ; Protein Conformation ; Protein Structure, Secondary

The in vivo assembly of ribosomal subunits is a highly complex process, with a tight coordination between protein assembly and rRNA maturation events, such as folding and processing of rRNA precursors, as well as modifications of selected bases. In the cell, a large number of factors are required to ensure the efficiency and fidelity of subunit production. Here we characterize the immature 30S subunits accumulated in a factor-null Escherichia coli strain (∆rsgA∆rbfA). The immature 30S subunits isolated with varying salt concentrations in the buffer system show interesting differences on both protein composition and structure. Specifically, intermediates derived under the two contrasting salt conditions (high and low) likely reflect two distinctive assembly stages, the relatively early and late stages of the 3' domain assembly, respectively. Detailed structural analysis demonstrates a mechanistic coupling between the maturation of the 5' end of the 17S rRNA and the assembly of the 30S head domain, and attributes a unique role of S5 in coordinating these two events. Furthermore, our structural results likely reveal the location of the unprocessed terminal sequences of the 17S rRNA, and suggest that the maturation events of the 17S rRNA could be employed as quality control mechanisms on subunit production and protein translation.
Cryoelectron Microscopy ; Escherichia coli ; metabolism ; Escherichia coli Proteins ; genetics ; metabolism ; GTP Phosphohydrolases ; genetics ; metabolism ; Mass Spectrometry ; Protein Structure, Secondary ; Protein Structure, Tertiary ; RNA, Ribosomal ; analysis ; metabolism ; Ribosomal Proteins ; chemistry ; genetics ; metabolism ; Ribosome Subunits, Small, Bacterial ; chemistry ; metabolism ; ultrastructure ; Salts ; chemistry

PURPOSE: Mitofusin2 gene (Mfn2, also named Hyperplasia suppressive gene, HSG) is very important in the origin and development of hypertension. However, the mechanism of Mfn2/HSG expression regulation was not uncovered. This study was designed to explore the association of a novel 5'-uncoding region (UCR) -1248 A>G variation of HSG/Mfn2 gene and hypertension. MATERIALS AND METHODS: 472 healthy, normotensive subjects [normotension (NT) group], 454 prehypertensive subjects [prehypertension (PH) group] and 978 hypertensive patients [essential hypertension (EH) group] were screened for an association study between 5'-UCR -1248 A>G of Mfn2/HSG and hypertension by polymerase chain reaction and DNA sequencing after venous blood was drawn and DNA was extracted. RESULTS: When comparing the A and G frequency in EH, PH and NT groups, in total, NT group significantly had higher A frequency than in PH group [odds ratio (OR)=1.605, confidence interval (CI) 95%=1.063-2.242, p=0.025] and EH group (OR=5.395, CI 95%=3.783-7.695, p<0.01). When subgrouped by gender, A frequency in NT group was still significantly higher than in EH group (male: OR=4.264, CI 95%=2.780-6.543, p<0.01; female: OR=8.897, CI 95%=4.686-16.891, p<0.01), but not from PH group, either in male group or in female group. Ordinal Logistic Regression analysis showed that A>G variation was significantly related with blood pressure level (B=-1.271, Wald=40.914, CI 95%=-1.660 - -0.881, p<0.01). CONCLUSION: 5'-UCR -1248 A>G variation of Mfn2/HSG gene was a novel variation and may be associated with hypertension in Chinese.
China ; Female ; GTP Phosphohydrolases/*genetics ; Gene Expression Regulation ; Genetic Association Studies ; Genotype ; Humans ; Hypertension/*genetics ; Logistic Models ; Male ; Mitochondrial Proteins/*genetics ; *Polymorphism, Single Nucleotide ; Sequence Analysis, DNA