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Transcription and replication of mitochondrial DNA (mtDNA) are regulated by nuclear DNA-encoded proteins that are targeted into mitochondria. A decrease in mtDNA copy number results in mitochondrial dysfunction, which may lead to insulin... more
Transcription and replication of mitochondrial DNA (mtDNA) are regulated by nuclear DNA-encoded proteins that are targeted into mitochondria. A decrease in mtDNA copy number results in mitochondrial dysfunction, which may lead to insulin resistance and metabolic syndromes. We analyzed mitochondrial proteins that physically bind to human mitochondrial D-loop DNA using a shot-gun proteomics approach following protein enrichment by D-loop DNA-linked affinity chromatography. A total of 152 D-loop DNA binding proteins were identified by peptide sequencing using ultra high pressure capillary reverse-phase liquid chromatography/tandem mass spectrometry. Bioinformatic analysis showed that 68 were mitochondrial proteins, 96 were DNA/RNA/protein binding proteins and 114 proteins might form a complex via protein-protein interactions. Histone family members of H1, H2A, H2B, H3, and H4, were detected in abundance among them. In particular, histones H2A and H2B were present in the mitochondrial membrane as integral membrane proteins and not bound directly to mtDNA inside the organelle. Histones H1.2, H3 and H4 were associated with the outer mitochondrial membrane. Silencing of H2AX expression inhibited mitochondrial protein transport. Our data suggests that many mitochondrial proteins may reside in multiple subcellular compartments like H2AX and exert multiple functions.
Research Interests: Mass Spectrometry, Biology, Proteomics, Apoptosis, Medicine, and 15 moreMitochondrial DNA, Humans, Cytochrome C, Chromatin, Nucleoids, Histones, Amino Acid Sequence, Histone, Protein Binding, Proteome, Protein Transport, Biochemistry and cell biology, Mitochondrial Proteins, Molecular Sequence Data, and mtDNA control region
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Research Interests: Iconography and Ischemia
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This paper describes a miniaturized oxygen sensor array integrated with heaters and temperature sensors and a LabVIEW-based measurement system which exactly can measure a cellular respiration level in a solution containing cells... more
This paper describes a miniaturized oxygen sensor array integrated with heaters and temperature sensors and a LabVIEW-based measurement system which exactly can measure a cellular respiration level in a solution containing cells simultaneously. The designed oxygen sensor consists of Clark-type sensors, heaters, and temperature sensors of 2 times 3 array type on the substrate. 18 mum PDMS was used for a permeable membrane of Clark-type sensor. The 90% response time was about 10 sec from full-oxygen (air-saturated) state to zero-oxygen (0.1 M Na2SO3) state. The fabricated sensor showed good reproducibility for 1 hour with 3.15 nA standard deviation of 108.2 nA mean in the full-oxygen state and 0.14 nA standard deviation of 1.33 nA mean in the zero-oxygen state. Also, the fabricated sensor showed a good linearity with a correlation coefficient of 0.997. The LabVIEW-based measurement system composed to voltage supply module, amplifier module, DMM module, and temperature sensing module. In order to measure the cellular respiration level, the measurement program using LabVIEW was made. The ratio of uncoupled cellular oxygen consumption rate per coupled cellular oxygen consumption rate obtained by the fabricated sensors showed 1.96 which is almost the same as the value obtained from a commercial Oxygen-2 K.
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Serum factors stimulate low density lipoprotein receptor (LDLR) gene expression in HepG2 cells through sterol-independent pathways. Promoter element other than sterol regulatory element-1 (SRE-1) seems to be necessary. Protein binding... more
Serum factors stimulate low density lipoprotein receptor (LDLR) gene expression in HepG2 cells through sterol-independent pathways. Promoter element other than sterol regulatory element-1 (SRE-1) seems to be necessary. Protein binding activity of the human LDLR promoter fragment (550bp) beyond the SRE-1 was determined by DNase I footprint assay. Five different promoter regions were protected from DNase I digestion; -226 to -258, -291 to -304, -324 to -336, -360 to -373, and -521 to -528. The regions of -324 to -336 and -521 to -528 showed serum response element (SRE)-like consensus sequence of CC(A/T)6GG. Serum incubation affected the protection degree of the SRE-like elements, but 25-hydroxycholesterol did not. It is proposed, therefore, that the promoter region of -324 to -336 and/or -521 to -528 showed serum response elements, but 25-hydroxycholesterol did not. It is proposed, therefore, that the promoter region of -324 to -336 and/or -521 to -528 in human LDLR gene may be responsible for the rapid activation of the gene transcription by serum factor in a sterol-independent manner.
Research Interests: Chemistry, Molecular Biology, Biology, Transcription Factors, Medicine, and 15 moreHumans, Pubmed, Promoter, Transcription Factor, Sterols, Base Sequence, LDL-Receptor, Sterol, Protein Binding, DNA binding proteins, DNA-footprinting, Serum response factor, Biochemistry and cell biology, Gene Expression Regulation, and Molecular Sequence Data
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Parkinson's disease (PD) is a multifactorial neurodegenerative disease with damages to mitochondria and endoplasmic reticulum (ER), followed by neuroinflammation. We previously reported that a triple herbal extract DA-9805 in... more
Parkinson's disease (PD) is a multifactorial neurodegenerative disease with damages to mitochondria and endoplasmic reticulum (ER), followed by neuroinflammation. We previously reported that a triple herbal extract DA-9805 in experimental PD toxin-models had neuroprotective effects by alleviating mitochondrial damage and oxidative stress. In the present study, we investigated whether DA-9805 could suppress ER stress and neuroinflammation in vitro and/or in vivo. Pre-treatment with DA-9805 (1 μg/ml) attenuated upregulation of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase-3 in SH-SY5Y neuroblastoma cells treated with thapsigargin (1 µg/ml) or tunicamycin (2 µg/ml). In addition, DA-9805 prevented the production of IL-1β, IL-6, TNF-α and nitric oxide through inhibition of NF-κB activation in BV2 microglial cells stimulated with lipopolysaccharides (LPS). Intraperitoneal injection of LPS (10 mg/kg) into mice can induce acute neuroinflammation and dopaminergic neuronal cell death. Oral administration of DA-9805 (10 or 30 mg/kg/day for 3 days before LPS injection) prevented loss of dopaminergic neurons and activation of microglia and astrocytes in the substantia nigra in LPS-injected mouse models. Taken together, these results indicate that DA-9805 can effectively prevent ER stress and neuroinflammation, suggesting that DA-9805 is a multitargeting and disease-modifying therapeutic candidate for PD.
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The nuclear DNA-encoded mitochondrial transcription factor A (TFAM) is synthesized in cytoplasm and transported into mitochondria. TFAM enhances both transcription and replication of mitochondrial DNA. It is unclear, however, whether TFAM... more
The nuclear DNA-encoded mitochondrial transcription factor A (TFAM) is synthesized in cytoplasm and transported into mitochondria. TFAM enhances both transcription and replication of mitochondrial DNA. It is unclear, however, whether TFAM plays a role in regulating nuclear gene expression. Here, we demonstrated that TFAM was localized to the nucleus and mitochondria by immunostaining, subcellular fractionation, and TFAM-green fluorescent protein hybrid protein studies. In HT22 hippocampal neuronal cells, human TFAM (hTFAM) overexpression suppressed human Tfam promoter-mediated luciferase activity in a dose-dependent manner. The mitochondria targeting sequence-deficient hTFAM also repressed Tfam promoter activity to the same degree as hTFAM. It indicated that nuclear hTFAM suppressed Tfam expression without modulating mitochondrial activity. The repression required for nuclear respiratory factor-1 (NRF-1), but hTFAM did not bind to the NRF-1 binding site of its promoter. TFAM was co-immunoprecipitated with NRF-1. Taken together, we suggest that nuclear TFAM down-regulate its own gene expression as a NRF-1 repressor, showing that TFAM may play different roles depending on its subcellular localizations.
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Research Interests: Endocrinology, Biology, Atherosclerosis, Adolescent, Cardiovascular disease, and 15 moreMedicine, Gene expression, Insulin Resistance, Humans, Internal Medicine, Cholesterol, Female, Body Mass Index, Homocysteine, Clinical Sciences, Adult, Cardiovascular Diseases, Leukocytes, hyperhomocysteinemia, and Cardiovascular medicine and haematology
Cyclophilin A (CypA), a member of the immunophilin family, is predominantly localized in the cytoplasm. The peptidylprolyl isomerase (PPIase) activity of CypA has been demonstrated to be involved in diverse cellular processes, including... more
Cyclophilin A (CypA), a member of the immunophilin family, is predominantly localized in the cytoplasm. The peptidylprolyl isomerase (PPIase) activity of CypA has been demonstrated to be involved in diverse cellular processes, including intracellular protein trafficking, mitochondrial function, pre-mRNA processing, and maintenance of multiprotein complex stability. In this study, we have demonstrated that CypA regulates apoptosis signaling-regulating kinase 1 (ASK1) through its direct binding. ASK1 is a member of MAPK kinase kinase (MAP3K) family, and selectively activates both JNK and p38 MAPK pathways. Here, we also report that CypA negatively regulates phosphorylation of ASK1 at Ser966, and that CypA reduces ASK1 and its downstream kinases of the JNK and p38 signaling. ASK1 is known to induce caspase-3 activation and apoptosis, and CypA inhibited ASK1-mediated apoptosis by decrease in caspase-3 activity under cellular stress conditions. Overall, we conclude that CypA negatively regulates ASK1 functions by its physical interaction with ASK1.
Research Interests: Chemistry, Cell Biology, Oxidative Stress, Medicine, MAP Kinase pathway and its regulation, and 15 moreSignal Transduction, Humans, Phosphorylation, Plasmids, Caspase, Kinase, Hydrogen Peroxide, Transfection, Protein Binding, Biochemistry and cell biology, Gene Expression Regulation, Ask, Cyclophilin A, binding sites, and Medical biochemistry and metabolomics
Research Interests: Biology, Cell Biology, Mitochondria, Endoplasmic Reticulum Stress, Apoptosis, and 15 moreMedicine, Cell line, Humans, Insulin, Endoplasmic Reticulum, Neurons, Herbicides, Microarray Analysis, Atrazine, Oxygen Consumption, Neurosciences, Biochemistry and cell biology, Adenosine Triphosphate, Mitochondrion, and coloring agents
Research Interests: Endocrinology, Biology, Medicine, Insulin Resistance, Malnutrition, and 15 moreMitochondrial DNA, Humans, Diabetes mellitus, Female, Fetal Growth, Mitochondrial dysfunction, Nutritional Biochemistry, Food Sciences, Base Sequence, Epidemiologic Studies, Glucose Intolerance, Nucleic Acid Conformation, Nucleotides, Biochemistry and cell biology, and Molecular Sequence Data
Research Interests: Molecular Biology, Biology, DNA damage, Medicine, Gene expression, and 15 moreMitochondrial DNA, Humans, Diabetes mellitus, Methylation, Animals, Cell, DNA methylation, Clinical Sciences, Hydrogen Peroxide, Amino Acid Sequence, Base Sequence, DNA binding proteins, Binding affinity, Mitochondrial Proteins, and Molecular Sequence Data
Research Interests: Molecular Biology, Biology, Biophysical Chemistry, Transcription Factors, Medicine, and 14 moreGene Silencing, Mitochondrial DNA, Methylation, DNA methylation, Promoter, Transcription Factor, Hepatoblastoma, Human Disease, DNA binding proteins, Binding Site, Biochemistry and cell biology, Down-Regulation, Mitochondrial Proteins, and Medical biochemistry and metabolomics
We investigated the effects of carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), a protonophore and uncoupler of mitochondrial oxidative phosphorylation in mitochondria, on plasma membrane potential and ionic currents in bovine... more
We investigated the effects of carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), a protonophore and uncoupler of mitochondrial oxidative phosphorylation in mitochondria, on plasma membrane potential and ionic currents in bovine aortic endothelial cells (BAECs). The membrane potential and ionic currents of BAECs were recorded using the patch-clamp technique in current-clamp and voltage-clamp modes, respectively. FCCP activated ionic currents and depolarized the plasma membrane potential in a dose-dependent manner. Neither the removal of extracellular Ca2+ nor pretreatment with BAPTA/AM affected the FCCP-induced currents, implying that the currents are not associated with the FCCP-induced intracellular [Ca2+]i increase. FCCP-induced currents were significantly influenced by the changes in extracellular or intracellular pH; the increased proton gradient produced by lowering the extracellular pH or intracellular alkalinization augmented the changes in membrane potential and ionic currents caused by FCCP. FCCP-induced currents were significantly reduced under extracellular Na+-free conditions. The reversal potentials of FCCP-induced currents under Na+-free conditions were well fitted to the calculated equilibrium potential for protons. Interestingly, FCCP-induced Na+ transport (subtracted currents, I(control)- I(Na+-free) was closely dependent on extracellular pH, whereas FCCP-induced H+transport was not significantly affected by the absence of Na+. These results suggest that the FCCP-induced ionic currents and depolarization, which are strongly dependent on the plasmalemmal proton gradient, are likely to be mediated by both H+ and Na+ currents across the plasma membrane. The relationship between H+ and Na+ transport still needs to be determined.
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Research Interests: Biochemistry, Chemistry, Magnetic Resonance Spectroscopy, Medicine, Micelle, and 13 moreMicelles, Animals, Peptide, Rats, Protein Conformation, SIGNAL PEPTIDE, Amino Acid Sequence, Aldehyde Dehydrogenase, Structural model, Biochemistry and cell biology, Molecular Sequence Data, phosphorylcholine, and Medical biochemistry and metabolomics
Research Interests: Biology, Drug development, Medicine, Western blotting, Lipopolysaccharide, and 15 moreRNA interference, Mice, Animals, Osteoclasts, Creatine Kinase, RANKL, Mouse Model, Bone Loss, Bone remodeling, Two-Dimensional Gel Electrophoresis, Enzymatic Activity, Two dimensional Gel Electrophoresis, Bone Resorption, reverse transcriptase polymerase chain reaction, and Medical and Health Sciences
Research Interests: Endocrinology, Diabetes, Anthropometry, Insulin Resistance, Adipose tissue, and 15 moreHumans, Hyperglycemia, Blood Glucose, Insulin, Glucagon, Diabetes mellitus, Female, Body Mass Index, Clinical Sciences, Homeostasis, Adult, Glucose Tolerance Test, Glucose Intolerance, Diabetes Care, and C Peptide
Research Interests: Chemistry, Biomarkers, Oxidative Stress, Mitochondria, Apoptosis, and 15 moreMedicine, Multidisciplinary, Cell line, Reactive Oxygen Species, Mice, Animals, Cytochrome C, Osteoblast, Environmental Health Engineering science, Environmental Pollutants, Osteoblasts, Cell Survival, Tetrabromobisphenol A, Cardiolipin, and Cell culture techniques
Research Interests: Endocrinology, Persistent Organic Pollutants, Endocrinology & Metabolism, Medicine, Metabolic syndrome, and 11 moreInternal Medicine, Diabetes mellitus, Body Mass Index, Aryl Hydrocarbon Receptor, Receptors, Odds ratio, Endocrinology and Diabetes, Glucose Intolerance, Confidence Interval, Dioxins, and Quartile
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Research Interests: Engineering, Materials Science, Technology, Nanotechnology, Medicine, and 14 moreZinc Oxide, Animals, Nanotubes, Nanorod, CHEMICAL SCIENCES, Swine, Immunoassay, Electrodes, Equipment Design, Equipment Failure Analysis, Biosensing Techniques, Nanoscience and nanotechnology, Viral Load, and conductometry
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Some genetic diseases are associated with the defects of the mitochondrial genome. Direct DNA delivery to the mitochondrial matrix has been suggested as an approach for mitochondrial gene therapy for these diseases. We hypothesized that a... more
Some genetic diseases are associated with the defects of the mitochondrial genome. Direct DNA delivery to the mitochondrial matrix has been suggested as an approach for mitochondrial gene therapy for these diseases. We hypothesized that a mitochondrial leader peptide (LP) conjugated polyethylenimine (PEI) could deliver DNA to the mitochondrial sites. PEI-LP was synthesized by the conjugation of LP to PEI using disulfide bond. The complex formation of PEI-LP with DNA was confirmed by a gel retardation assay. In this study, DNA was completely retarded at a 0.4/1 PEI-LP/DNA weight ratio. In vitro delivery tests into isolated mitochondria or living cells were performed with rhodamin-labeled DNA and PEI-LP. In vitro cell-free delivery assay with isolated mitochondria showed that PEI-LP/DNA complexes were localized at mitochondria sites. Furthermore, the PEL-LP/DNA complexes were localized at the mitochondrial sites in living cells. However, a control carrier, PEI, did not show this effect. In addition, MTT assay showed that PEI-LP showed lower cytotoxicity than PEI. These results suggest that PEI-LP can deliver DNA to the mitochondrial sites and may be useful for the development of mitochondrial gene therapy.
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Research Interests: Endocrinology, Flow Cytometry, Biology, Cell Division, Growth Hormone, and 15 moreInternal Medicine, Kidney, Insulin, Cartilage, Animals, Drug Resistance, Male, Fibroblast Growth Factor, Blood Urea Nitrogen, Clinical Sciences, Chronic Renal Failure, Growth Factor, Epiphyses, Chondrocyte, and Cell Size
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Research Interests: Technology, Senescence, Biology, Mitochondria, Medicine, and 14 moreGene expression, Biological Sciences, Gestational diabetes, Cell Differentiation, Pregnancy, Humans, Female, Adipogenesis, Mesenchymal Stem Cell, Oxidative phosphorylation, Cell Proliferation, Umbilical Cord, Mesenchymal Stromal Cells, and Medical and Health Sciences
We previously showed that incubation of rat liver motochondria with alcohols resulted in the inhibition of the import of aldehyde dehydrogenase precursor but not that of ormithine transcarbamylase precursor (Wang TTY, Farrés J, and Weiner... more
We previously showed that incubation of rat liver motochondria with alcohols resulted in the inhibition of the import of aldehyde dehydrogenase precursor but not that of ormithine transcarbamylase precursor (Wang TTY, Farrés J, and Weiner H: Arch Biochem Biophys 272:440–449, 1989). The time required for inhibition of import to occur was now measured with ethanol (200 mM) and butanol (100 mM) at 0° and 30°C. It required approximately 30 min to achieve 50% inhibition with butanol and 50 min with ethanol. To further substantiate the membrane perturbing effects of alcohols, we also examined the effect of oleic acid on import. We found that incubation of mitochondria with oleic acid (0–100 μM) resulted in inhibition of aldehyde dehydrogenase precursor import in a dose response fashion. In addition to in vitro effects of alcohols on import, we conducted a preliminary study on import of protein into liver mitochondria isolated from rats fed ethanol. We found that the rate of aldehyde dehydrogenase precursor import into liver mitochondria isolated from ethanol fed rats was identical to that from control. The results are consistent with finding that the activity and amount of aldehyde dehydrogenase was the same in mitochondria isolated from the alcohol‐fed or control animals.
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It is generally accepted that mitochondrial deficits cause many common age-associated diseases including type 2 diabetes. However, it has not been understood what causes mitochondrial damages and how to interrupt the development of the... more
It is generally accepted that mitochondrial deficits cause many common age-associated diseases including type 2 diabetes. However, it has not been understood what causes mitochondrial damages and how to interrupt the development of the diseases in patients. Recent epidemiologic studies demonstrated a positive correlation between serum concentrations of environmental pollutants and insulin resistance/diabetes. Emerging data strongly suggest that some synthetic pollutants disturb the signaling pathway critical for energy homeostasis and insulin action. The synthetic chemicals are possibly involved in pathogenesis of insulin resistance and diabetes as mitochondria-disturbing agents. In this review, we present a molecular scheme to address the contribution of environmental synthetic chemicals to this metabolic catastrophe. Efforts to identify synthetic chemicals with mitochondria-damaging activities may open a new era to develop effective therapeutic interventions against the worldwide-spreading metabolic disorder.
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Abstract In our previous study, 20 nm-sized amorphous silica nanoparticles (20-SiNPs), but not 50 nm-sized amorphous silica nanoparticles (50-SiNPs), induced pulmonary inflammatory response in rats exposed repeatedly for 14 days (12.5,... more
Abstract In our previous study, 20 nm-sized amorphous silica nanoparticles (20-SiNPs), but not 50 nm-sized amorphous silica nanoparticles (50-SiNPs), induced pulmonary inflammatory response in rats exposed repeatedly for 14 days (12.5, 25, and 50 μg/time, total six times). In this study, we tried to clarify the causes of different responses induced by both SiNPs using mice (12.5, 25, and 50 μg/lung) and mouse alveolar macrophage cells. When exposed to alveolar macrophage cells for 24 h, both SiNPs decreased cell viability and enhanced ROS generation compared to controls. The 20- and 50-SiNPs also formed giant and autophagosome-like vacuoles in the cytoplasm, respectively. Structural damage of organelles was more pronounced in 20-SiNPs-treated cells than in 50-SiNPs-treated cells, and an increased mitochondrial membrane potential and mitochondrial calcium accumulation were observed only in the 20-SiNPs-treated cells. Additionally, a single intratracheal instillation of both sizes of SiNPs to mice clearly elevated the relative proportion of neutrophils and inhibited differentiation of macrophages and expression of an adhesion molecule. Meanwhile, interestingly, the total number of pulmonary cells and the levels of pro-inflammatory mediators more notably increased in the lungs of mice exposed to 20-SiNPs compared to 50-SiNPs. Given that accumulation of giant vacuoles and dilation of the ER and mitochondria are key indicators of paraptosis, we suggest that 20-SiNPs-induced pulmonary inflammation may be associated with paraptosis of alveolar macrophages.
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Research Interests: Pharmacology, Chemistry, Magnetic Resonance Spectroscopy, Medicine, Mice, and 12 moreAnimals, Drug Design, Peroxisome proliferator-activated receptor, Plasmids, Oral Hypoglycemic Agents, Quercetin, Peroxisome, Transfection, Rosiglitazone, Structure activity Relationship, fibroblasts, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, Biomarkers, Oxidative Stress, Mitochondria, Apoptosis, and 15 moreMedicine, Multidisciplinary, Cell line, Reactive Oxygen Species, Mice, Animals, Cytochrome C, Osteoblast, Environmental Pollutants, Osteoblasts, Cell Survival, Journal of Environmental Health Science and Engineering, Tetrabromobisphenol A, Cardiolipin, and Cell culture techniques
: Mitochondrial dysfunction has been suggested as a causal factor for insulin resistance and diabetes. Previously we have shown a decrease of mitochondrial DNA (mtDNA) content in tissues of diabetic patients. The mitochondrial proteins,... more
: Mitochondrial dysfunction has been suggested as a causal factor for insulin resistance and diabetes. Previously we have shown a decrease of mitochondrial DNA (mtDNA) content in tissues of diabetic patients. The mitochondrial proteins, which regulate the mitochondrial biogensis, including transcription and replication of mtDNA, are encoded by nuclear DNA. Despite the potential function of the proteins bound to the D‐loop region of mtDNA in regulating mtDNA transcription/replication, only a few proteins are known to bind the D‐loop region of mtDNA. The functional association of these known proteins with insulin resistance is weak. In this study, we applied proteomic analysis to identify a group of proteins (proteome) that physically bind to D‐loop DNA of mtDNA. We amplified D‐loop DNA (1.1 kb) by PCR and conjugated the PCR fragments to CNBr‐activated sepharose. Mitochondria fractions were isolated by both differential centrifugation and Optiprep‐gradient ultracentrifugation. The D‐loop DNA binding proteome fractions were enriched via this affinity chromatography and analyzed by SDS‐PAGE. The proteins on the gel were transferred onto PVDF membrane and the peptide sequences of each band were subsequently analyzed by capillary reverse‐phase liquid chromatography/tandem mass spectrometry (RPLC/MS/MS). We identified many D‐loop DNA binding proteins, including mitochondrial transcription factor A (mtTFA, Tfam) and mitochondrial single‐stranded DNA binding protein (mtSSBP) which were known to bind to mtDNA. We also report the possibility of novel D‐loop binding proteins such as histone family proteins and high‐mobility group proteins.
Research Interests: Molecular Biology, Mass Spectrometry, Biology, Medicine, Multidisciplinary, and 15 moreCell line, Mitochondrial DNA, Humans, Tandem Mass Spectrometry, Affinity chromatography, Transcription Factor, nuclear DNA, Mitochondrial dysfunction, Potential Function, DNA binding, Proteome analysis, Amino Acid Sequence, Proteome, Mitochondrial Proteins, and Molecular Sequence Data
Research Interests: Biology, Mitochondria, Medicine, Cell line, Mitochondrial DNA, and 15 moreHumans, MITOCHONDRIAL BIOGENESIS, Mitochondrial dysfunction, Genomic DNA, Ethnic Group, Hepatocytes, Heat Shock Proteins, Glycine, Protein Binding, DNA binding proteins, Biochemistry and cell biology, Mitochondrial Proteins, binding sites, Medical biochemistry and metabolomics, and Peripheral blood
: Insulin resistance has been recognized as the fundamental underlying metabolic defect in the pathogenesis of metabolic syndrome, a clustering of cardiovascular risk factors such as diabetes, hypertension, dyslipidemia, and obesity.... more
: Insulin resistance has been recognized as the fundamental underlying metabolic defect in the pathogenesis of metabolic syndrome, a clustering of cardiovascular risk factors such as diabetes, hypertension, dyslipidemia, and obesity. Recent studies established that mitochondrial dysfunction is involved in insulin resistance in general and fetal origin of this state in particular. Because genes are the fundamental molecular basis of inheritance—and thus the cornerstones of evolution—a model explaining insulin resistance is based at the gene level at best. Since a certain mtDNA polymorphism, 16189T>C, is associated with insulin resistance, mtDNA has to be a basic component of the gene‐based model. We developed a mitochondria‐based model that explains insulin resistance in terms of quantitative and qualitative change of the mitochondrion and its DNA. This model can accommodate several important hypotheses, such as thrifty genotype hypothesis, thrifty phenotype hypothesis, fetal insulin hypothesis, contribution of metabolic imprinting by epigenetic changes, and many other features associated with insulin resistance. We will discuss mechanisms that indicate why the perturbed initial condition of mitochondrial function should lead to the reduced insulin sensitivity.