UCP3 protein, human OR C000604392 Dotaz Zobrazit nápovědu
- MeSH
- adenosintrifosfát farmakologie metabolismus MeSH
- guanosintrifosfát farmakologie metabolismus MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- nenasycené mastné kyseliny metabolismus MeSH
- proteiny metabolismus MeSH
- transportní proteiny metabolismus MeSH
- ubichinon analogy a deriváty MeSH
- Check Tag
- lidé MeSH
Uncoupling proteiny jsou mitochondriální bílkoviny odpřahující tvorbu ATP od dýchacího řetězce. Dosud jich bylo objeveno několik, nejvíce prozkoumán je UCP1. Je exprimován v hnědé tukové tkáni a jeho funkcí je tvorba tepla. Termogenní funkce této tkáně je známa již delší dobu, u člověka však hnědý tuk obvykle zaniká již v dětství. V dospělosti v lidském organizmu najdeme UCP2 a UCP3. Předpokládá se, že tyto bílkoviny ovlivňují metabolizmus lipidů a energetický výdej, proto se zkoumá jejich možné využití v terapii obezity. Přesná fyziologická funkce v organizmu však dosud nebyla vysvětlena.
Uncoupling proteins are located in the inner mitochondria membrane. Their name is derived from their function: they uncouple oxidative processes of the respiratory chain from ATP synthesis. Hitherto several members of the family have been described, the best known being UCP1. UCP1 can be expressed exclusively in brown adipose tissue and it is responsible for the heat production. In humans the brown fat disappears during the early childhood. In adults another members of the UCP family can be found - UCP2 and UCP3. It is widely accepted that these proteins affect lipid metabolism and energy expenditure. They are intensively studied owing to their possible use in the therapy of obesity. However, their physiological function has not been yet fully established.
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : tab., grafy ; 30 cm
Mitochondrial "uncoupling proteins"(UCPs) are important regulators of the efficiency of energy conversion.Expression of UCPs in various tissues changes rapidly during the perinatal development. Specific aims:(1) To characterise in detail the liver UCP2 expression in premature human newborns, in the relationship to pre- and postnatal infection. (2) To learn whether UCP2 expression in myelocytes is affected by antidiabetics (thiazolidinediones). To describe the postnatal development of UCP3 in human skeletal muscle, in the relationship to the nutrition.The unique collection of autoptic samples of human newborn tissues will be used and new samples will be collected. Methodical approaches: (1) immunohistocxhemistry and in situ hybridisation,for identification of the cell types with UCP2 and UCP3 expression;and Real-Time RT-PCR for highly sensitive and accurate quantification of gene expression.
Mitochondriální "rozpřahující proteiny" (UCP) jsou důležité regulátory účinností energentické přeměny v mitochondriích.V průběhu perinatálního období se exprese genů UCP v tkáních výrazně mění. Cíle projektu:(1) Detailně charekterizovat expresi UCP2 v játrech nedonošených dětí, v závislosti na pre- a postnatální infekci.(2) Ověřit možnost ,odulace UCP2 v myeloidních buňkách vlivem antidiabetik (thiazolidinedionů). Popsat postnatální vývoj UCP3 v lidském svalu v závislosti na výživě.Bude využita unikátníkolekce autoptických vzorků z tkání lidských novorozenců a sběr bude dále rozšířen.Pokusy proběhnou také na myších. Metodické přístupy:imunohistochemie a in situ hybridizace pro identifikaci typů buněk s expresí UCP2 a UCP3; a technika "real-time"RT-PCRpro vysoce citlivou a přesnou analýzu genové exprese.
- MeSH
- energetický metabolismus MeSH
- játra MeSH
- kosterní svaly MeSH
- mitochondrie MeSH
- nemoci nedonošenců MeSH
- nemoci novorozenců MeSH
- novorozenec nedonošený metabolismus MeSH
- novorozenec metabolismus MeSH
- oxidativní fosforylace MeSH
- plod metabolismus MeSH
- rozpřahující látky MeSH
- transportní proteiny genetika metabolismus MeSH
- Check Tag
- novorozenec metabolismus MeSH
The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of α-ketoglutarate dehydrogenase complex (αKGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid β-methyl ester (mAsp) and dimethyl α-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1α) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC.
- MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků MeSH
- doxycyklin farmakologie MeSH
- gentisáty chemie farmakologie MeSH
- heterocyklické sloučeniny chemie farmakologie MeSH
- ketoglutarátdehydrogenasový komplex antagonisté a inhibitory genetika MeSH
- lidé MeSH
- mitochondrie účinky léků patologie MeSH
- nádory prsu farmakoterapie genetika patologie MeSH
- organofosforové sloučeniny chemie farmakologie MeSH
- oxidativní fosforylace účinky léků MeSH
- proliferace buněk účinky léků MeSH
- proteinkinasy genetika MeSH
- proteosyntéza účinky léků MeSH
- ribozomy účinky léků MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function. METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty. Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day. ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data. Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 ± 0.94, day 7 = - 0.47 ± 1.04 mean log2 fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 ± 0.67, day 7 = 0.07 ± 1.65 mean log2 fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 ± 0.50, day 7 = 0.97 ± 0.76 mean log2 fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences. Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P < 0.001), SLC25A20 (P = 0.017) and UCP3 (P < 0.001) decreased between admission and day 7 in both arms. LPIN-1 (P < 0.001) and SPT1 (P = 0.044) decreased between admission and day 7. IL-18 (P = 0.011) and TNFRSF12A (P = 0.009) increased in both arms between admission and day 7. IL-1β (P = 0.007), its receptor IL-1R1 (P = 0.005) and IL-6R (P = 0.001) decreased in both arms between admission and day 7. No between group differences were seen in any of these (all p > 0.05). CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.
