Base de dados : MEDLINE
Pesquisa : G04.618 [Categoria DeCS]
Referências encontradas : 679 [refinar]
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[PMID]:28460056
[Au] Autor:Hayashi G; Jasoliya M; Sahdeo S; Saccà F; Pane C; Filla A; Marsili A; Puorro G; Lanzillo R; Brescia Morra V; Cortopassi G
[Ad] Endereço:Department of Molecular Biosciences, University of California, Davis, 95616 CA, USA.
[Ti] Título:Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans.
[So] Source:Hum Mol Genet;26(15):2864-2873, 2017 08 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMF's target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
[Mh] Termos MeSH primário: Fumarato de Dimetilo/metabolismo
Fator 2 Relacionado a NF-E2/metabolismo
[Mh] Termos MeSH secundário: Animais
Técnicas de Cultura de Células
Fumarato de Dimetilo/química
Fibroblastos
Fator de Transcrição de Proteínas de Ligação GA
Seres Humanos
Camundongos
Mitocôndrias/metabolismo
Esclerose Múltipla/metabolismo
Esclerose Múltipla/patologia
Fator 2 Relacionado a NF-E2/genética
Fármacos Neuroprotetores/farmacologia
Biogênese de Organelas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (GA-Binding Protein Transcription Factor); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (Neuroprotective Agents); 0 (Nfe2l2 protein, mouse); FO2303MNI2 (Dimethyl Fumarate)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx167


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[PMID]:29391135
[Au] Autor:Qi R; Wang D; Xing L; Wu Z
[Ad] Endereço:Departrment of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Departrment of Thoracic Surgery, Inner Mongolia People's Hospital, Hohhot City, Inner Mongolia, 010017, China.
[Ti] Título:Cyclosporin A inhibits mitochondrial biogenesis in Hep G2 cells.
[So] Source:Biochem Biophys Res Commun;496(3):941-946, 2018 02 12.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dysregulation of mitochondrial biogenesis is associated with pathogenesis in many diseases, including liver diseases. Cyclosporine A (CsA), one of the most commonly used drug to treat many autoimmune diseases and to prevent allograft rejection after organ transplantation, has been reported to cause mitochondrial dysfunction. However, the cellular mechanisms underlying CsA on mitochondrial dysfunction remain at present not completely elucidated. In this study, we found that CsA reduced the expression of PGC-1α at both the mRNA and protein levels in HepG2 cells. Correspondingly, the expressions of its target genes NRF 1 and TFAM were reduced in response to CsA treatment. In addition, mtDNA/nDNA, mitochondria mass, ATP production, and cytochrome C oxidase activity were significantly reduced by treatment with CsA. Over-expression of PGC-1α was found to rescue the negative effect of CsA administration on mitochondrial biogenesis. Mechanistically, CREB was involved in the inhibitory effects of CsA in mitochondrial biogenesis.
[Mh] Termos MeSH primário: Ciclosporina/administração & dosagem
Mitocôndrias Hepáticas/efeitos dos fármacos
Mitocôndrias Hepáticas/metabolismo
Proteínas Mitocondriais/metabolismo
Biogênese de Organelas
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Células Hep G2
Seres Humanos
Mitocôndrias Hepáticas/ultraestrutura
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mitochondrial Proteins); 83HN0GTJ6D (Cyclosporine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE


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[PMID]:28455453
[Au] Autor:Volodina O; Ganesan S; Pearce SC; Gabler NK; Baumgard LH; Rhoads RP; Selsby JT
[Ad] Endereço:Department of Animal Science, Iowa State University, Ames, Iowa.
[Ti] Título:Short-term heat stress alters redox balance in porcine skeletal muscle.
[So] Source:Physiol Rep;5(8), 2017 Apr.
[Is] ISSN:2051-817X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Heat stress contributes to higher morbidity and mortality in humans and animals and is an agricultural economic challenge because it reduces livestock productivity. Redox balance and associated mitochondrial responses appear to play a central role in heat stress-induced skeletal muscle pathology. We have previously reported increased oxidative stress and mitochondrial content in oxidative muscle following 12 h of heat stress. The purposes of this investigation were to characterize heat stress-induced oxidative stress and changes in mitochondrial content and biogenic signaling in oxidative skeletal muscle. Crossbred gilts were randomly assigned to either thermal neutral (21°C;  = 8, control group) or heat stress (37°C) conditions for 2 h ( = 8), 4 h ( = 8), or 6 h ( = 8). At the end, their respective environmental exposure, the red portion of the semitendinosus muscle (STR) was harvested. Heat stress increased concentration of malondialdehyde (MDA) following 2 and 4 h compared to thermal neutral and 6 h, which was similar to thermal neutral, and decreased linearly with time. Protein carbonyl content was not influenced by environment. Catalase activity was increased following 4 h of heat stress and superoxide dismutase activity was decreased following 6 h of heat stress compared to thermal neutral conditions. Heat stress-mediated changes in antioxidant activity were independent of altered protein abundance or transcript expression. Mitochondrial content and mitochondrial biogenic signaling were similar between groups. These data demonstrate that heat stress caused a transient increase in oxidative stress that was countered by a compensatory change in catalase activity. These findings contribute to our growing understanding of the chronology of heat stress-induced intracellular dysfunctions in skeletal muscle.
[Mh] Termos MeSH primário: Transtornos de Estresse por Calor/metabolismo
Músculo Esquelético/metabolismo
Doenças dos Suínos/metabolismo
[Mh] Termos MeSH secundário: Animais
Retículo Endoplasmático/fisiologia
Transtornos de Estresse por Calor/fisiopatologia
Temperatura Alta/efeitos adversos
Masculino
Mitocôndrias Musculares/metabolismo
Músculo Esquelético/fisiopatologia
Biogênese de Organelas
Oxirredução
Estresse Oxidativo/fisiologia
Fenótipo
Sus scrofa
Suínos
Doenças dos Suínos/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:28741661
[Au] Autor:Zhang C; Yang L; Zhao X; Chen X; Wang L; Geng Z
[Ad] Endereço:College of Animal Science and Technology, Anhui Agricultural University, Hefei, Anhui, China.
[Ti] Título:Effect of dietary resveratrol supplementation on meat quality, muscle antioxidative capacity and mitochondrial biogenesis of broilers.
[So] Source:J Sci Food Agric;98(3):1216-1221, 2018 Feb.
[Is] ISSN:1097-0010
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The naturally occurring polyphenol resveratrol has been acknowledged with many beneficial biological effects. The aim of this study was to evaluate the influence of dietary resveratrol supplementation on meat quality, muscle antioxidative capacity and mitochondrial biogenesis of broilers. One hundred and eighty 21-day-old male Cobb broilers were randomly assigned to two groups and fed on a 0 mg kg or 400 mg kg resveratrol-supplemented diet for 21 days. Then, chickens were slaughtered and pectoralis major muscle (PM) samples were collected for analysis. RESULTS: The results showed that resveratrol not only tended to increase (P < 0.10) PM pH but also significantly decreased (P < 0.05) PM L* , pH decline, drip loss and lactate content. Meanwhile, PM total antioxidative capacity and catalase activity were significantly increased (P < 0.05) by resveratrol, while malondialdehyde content was decreased (P < 0.10). Moreover, resveratrol significantly increased (P < 0.05) PM peroxisome proliferator-activated receptor γ coactivator 1α and nuclear respiratory factor 1 mRNA levels, along with increased (P < 0.05) citrate synthase activity. CONCLUSION: Resveratrol can be used as a feed additive to improve meat quality of broilers, which may be associated with improved muscle antioxidative status and mitochondrial biogenesis. © 2017 Society of Chemical Industry.
[Mh] Termos MeSH primário: Ração Animal/análise
Antioxidantes/análise
Galinhas/metabolismo
Suplementos Nutricionais/análise
Carne/análise
Mitocôndrias/metabolismo
Estilbenos/metabolismo
[Mh] Termos MeSH secundário: Animais
Antioxidantes/metabolismo
Masculino
Malondialdeído/metabolismo
Músculo Esquelético/química
Músculo Esquelético/metabolismo
Biogênese de Organelas
Estilbenos/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Stilbenes); 4Y8F71G49Q (Malondialdehyde); Q369O8926L (resveratrol)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1002/jsfa.8576


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[PMID]:29245012
[Au] Autor:Kater L; Thoms M; Barrio-Garcia C; Cheng J; Ismail S; Ahmed YL; Bange G; Kressler D; Berninghausen O; Sinning I; Hurt E; Beckmann R
[Ad] Endereço:Gene Center Munich and Center of Integrated Protein Science-Munich (CiPS-M), Department of Biochemistry, Feodor-Lynen-Str. 25, University of Munich, 81377 Munich, Germany.
[Ti] Título:Visualizing the Assembly Pathway of Nucleolar Pre-60S Ribosomes.
[So] Source:Cell;171(7):1599-1610.e14, 2017 Dec 14.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eukaryotic 60S ribosomal subunits are comprised of three rRNAs and ∼50 ribosomal proteins. The initial steps of their formation take place in the nucleolus, but, owing to a lack of structural information, this process is poorly understood. Using cryo-EM, we solved structures of early 60S biogenesis intermediates at 3.3 Å to 4.5 Å resolution, thereby providing insights into their sequential folding and assembly pathway. Besides revealing distinct immature rRNA conformations, we map 25 assembly factors in six different assembly states. Notably, the Nsa1-Rrp1-Rpf1-Mak16 module stabilizes the solvent side of the 60S subunit, and the Erb1-Ytm1-Nop7 complex organizes and connects through Erb1's meandering N-terminal extension, eight assembly factors, three ribosomal proteins, and three 25S rRNA domains. Our structural snapshots reveal the order of integration and compaction of the six major 60S domains within early nucleolar 60S particles developing stepwise from the solvent side around the exit tunnel to the central protuberance.
[Mh] Termos MeSH primário: Chaetomium/química
Biogênese de Organelas
Subunidades Ribossômicas Maiores de Eucariotos/química
[Mh] Termos MeSH secundário: Chaetomium/citologia
Microscopia Crioeletrônica
Redes e Vias Metabólicas
Modelos Moleculares
Dobramento de RNA
Ribonucleoproteínas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ribonucleoproteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180103
[Lr] Data última revisão:
180103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


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[PMID]:28455444
[Au] Autor:Serfass JM; Takahashi Y; Zhou Z; Kawasawa YI; Liu Y; Tsotakos N; Young MM; Tang Z; Yang L; Atkinson JM; Chroneos ZC; Wang HG
[Ad] Endereço:From the Department of Pharmacology.
[Ti] Título:Endophilin B2 facilitates endosome maturation in response to growth factor stimulation, autophagy induction, and influenza A virus infection.
[So] Source:J Biol Chem;292(24):10097-10111, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endocytosis, and the subsequent trafficking of endosomes, requires dynamic physical alterations in membrane shape that are mediated in part by endophilin proteins. The endophilin B family of proteins contains an N-terminal Bin/amphiphysin/Rvs (N-BAR) domain that induces membrane curvature to regulate intracellular membrane dynamics. Whereas endophilin B1 (SH3GLB1/Bif-1) is known to be involved in a number of cellular processes, including apoptosis, autophagy, and endocytosis, the cellular function of endophilin B2 (SH3GLB2) is not well understood. In this study, we used genetic approaches that revealed that endophilin B2 is not required for embryonic development but that endophilin B2 deficiency impairs endosomal trafficking , as evidenced by suppressed endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry and replication. Mechanistically, although the loss of endophilin B2 did not affect endocytic internalization and lysosomal function, endophilin B2 appeared to regulate the trafficking of endocytic vesicles and autophagosomes to late endosomes or lysosomes. Moreover, we also found that despite having an intracellular localization and tissue distribution similar to endophilin B1, endophilin B2 is dispensable for mitochondrial apoptosis. Taken together, our findings suggest that endophilin B2 positively regulates the endocytic pathway in response to growth factor signaling, autophagy induction, and viral entry.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Autofagia
Proteínas de Transporte/metabolismo
Endossomos/metabolismo
Fator de Crescimento Epidérmico/metabolismo
Receptor do Fator de Crescimento Epidérmico/agonistas
Transdução de Sinais
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/química
Proteínas Adaptadoras de Transdução de Sinal/genética
Animais
Apoptose
Proteínas de Transporte/química
Proteínas de Transporte/genética
Linhagem Celular
Células Cultivadas
Endocitose
Endossomos/virologia
Seres Humanos
Vírus da Influenza A/fisiologia
Camundongos Endogâmicos C57BL
Camundongos Knockout
Especificidade de Órgãos
Biogênese de Organelas
Transporte Proteico
Receptor do Fator de Crescimento Epidérmico/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Internalização do Vírus
Replicação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Carrier Proteins); 0 (Recombinant Fusion Proteins); 0 (SH3GLB2 protein, human); 0 (Sh3glb2 protein, mouse); 62229-50-9 (Epidermal Growth Factor); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171228
[Lr] Data última revisão:
171228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.792747


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[PMID]:29185343
[Au] Autor:Saihara K; Kamikubo R; Ikemoto K; Uchida K; Akagawa M
[Ad] Endereço:Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University , Sakai 599-8531, Japan.
[Ti] Título:Pyrroloquinoline Quinone, a Redox-Active o-Quinone, Stimulates Mitochondrial Biogenesis by Activating the SIRT1/PGC-1α Signaling Pathway.
[So] Source:Biochemistry;56(50):6615-6625, 2017 Dec 19.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrroloquinoline quinone (PQQ), a redox-active o-quinone found in various foods and mammalian tissues, has received an increasing amount of attention because of a number of health benefits that can be attributed to its ability to enhance mitochondrial biogenesis. However, its underlying molecular mechanism remains incompletely understood. We have now established that the exposure of mouse NIH/3T3 fibroblasts to a physiologically relevant concentration of PQQ significantly stimulates mitochondrial biogenesis. The exposure of NIH/3T3 cells to 10-100 nM PQQ for 48 h resulted in increased levels of Mitotracker staining, mitochondrial DNA content, and mitochondrially encoded cytochrome c oxidase subunit 1 (MTCO1) protein. Moreover, we observed that PQQ treatment induces deacetylation of the peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α) and facilitates its nuclear translocation and target gene expression but does not affect its protein levels, implying increased activity of the NAD -dependent protein deacetylase sirtuin 1 (SIRT1). Indeed, treatment with a SIRT1 selective inhibitor, EX-527, hampered the ability of PQQ to stimulate PGC-1α-mediated mitochondrial biogenesis. We also found that the PQQ treatment caused a concentration-dependent increase in the cellular NAD levels, but not the total NAD and NADH levels. Our results suggest that PQQ-inducible mitochondrial biogenesis can be attributed to activation of the SIRT1/PGC-1α signaling pathway by enhancing cellular NAD formation.
[Mh] Termos MeSH primário: Cofator PQQ/metabolismo
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
Sirtuína 1/metabolismo
[Mh] Termos MeSH secundário: Animais
Benzoquinonas/química
Benzoquinonas/metabolismo
Fibroblastos
Células Hep G2
Seres Humanos
Camundongos
Mitocôndrias/metabolismo
Mitocôndrias/fisiologia
Células NIH 3T3
Biogênese de Organelas
Oxirredução
Cofator PQQ/química
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética
Transdução de Sinais/efeitos dos fármacos
Sirtuína 1/genética
Transativadores/metabolismo
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Trans-Activators); 0 (Transcription Factors); 3T006GV98U (quinone); 72909-34-3 (PQQ Cofactor); EC 3.5.1.- (SIRT1 protein, human); EC 3.5.1.- (Sirt1 protein, mouse); EC 3.5.1.- (Sirtuin 1)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b01185


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[PMID]:28452586
[Au] Autor:Ortega SP; Chouchani ET; Boudina S
[Ad] Endereço:a Department of Nutrition and Integrative Physiology and Division of Endocrinology , Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine , Salt Lake City , Utah , USA.
[Ti] Título:Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes.
[So] Source:Adipocyte;6(1):56-61, 2017 01 02.
[Is] ISSN:2162-397X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Reactive oxygen species (ROS) production and oxidative stress (OS) in adipose tissue are associated with obesity and insulin resistance (IR). The nature of this relationship i.e., cause and effect or consequence has not been clearly determined. We provide evidence that elevated mitochondrial ROS generated by adipocytes from mice with diet-induced obesity (DIO) represents an adaptive mechanism that precipitates fatty acid oxidation, mitochondrial biogenesis, and mitochondrial uncoupling in an effort to defend against weight gain. Consistent with that, mice with adipocyte-specific deletion of manganese superoxide dismutase (MnSOD) exhibit increased adipocyte superoxide generation and are protected from weight gain and insulin resistance which otherwise develops in wild-type (WT) mice that consume an obesogenic diet. The defense mechanism displayed by MnSOD-deficiency in fat cells appears to be mediated by a dual effect of ROS on inefficient substrate oxidation through uncoupling of oxidative phosphorylation and enhanced mitochondrial biogenesis. The aim of this commentary is to summarize and contextualize additional evidence supporting the importance of mitochondrial ROS in the regulation of mitochondrial biogenesis and the modulation of uncoupling protein 1 (UCP1) expression and activation in both white and brown adipocytes.
[Mh] Termos MeSH primário: Adipócitos/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Superóxido Dismutase/metabolismo
Proteína Desacopladora 1/metabolismo
[Mh] Termos MeSH secundário: Adipócitos/efeitos dos fármacos
Animais
Metabolismo Energético/efeitos dos fármacos
Camundongos
Mitocôndrias/efeitos dos fármacos
Proteínas Mitocondriais/metabolismo
Biogênese de Organelas
Estresse Oxidativo/fisiologia
Superóxido Dismutase/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Mitochondrial Proteins); 0 (Reactive Oxygen Species); 0 (Uncoupling Protein 1); EC 1.15.1.1 (Superoxide Dismutase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171216
[Lr] Data última revisão:
171216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1080/21623945.2016.1273298


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[PMID]:29050400
[Au] Autor:Fitzgerald JC; Zimprich A; Carvajal Berrio DA; Schindler KM; Maurer B; Schulte C; Bus C; Hauser AK; Kübler M; Lewin R; Bobbili DR; Schwarz LM; Vartholomaiou E; Brockmann K; Wüst R; Madlung J; Nordheim A; Riess O; Martins LM; Glaab E; May P; Schenke-Layland K; Picard D; Sharma M; Gasser T; Krüger R
[Ad] Endereço:Department of Neurodegenerative Diseases, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen and German Centre for Neurodegenerative Diseases, Tübingen, Germany.
[Ti] Título:Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease.
[So] Source:Brain;140(9):2444-2459, 2017 Sep 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson's disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson's disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson's disease and provide new prospects for targeted therapies.
[Mh] Termos MeSH primário: Proteínas de Choque Térmico HSP90/genética
Metformina/uso terapêutico
Mitocôndrias/efeitos dos fármacos
Doença de Parkinson/tratamento farmacológico
Doença de Parkinson/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Apoptose/efeitos dos fármacos
Estudos de Casos e Controles
Células Cultivadas
Fibroblastos/metabolismo
Proteínas de Choque Térmico HSP90/biossíntese
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Potencial da Membrana Mitocondrial/fisiologia
Mitocôndrias/genética
Mitocôndrias/metabolismo
Proteínas Mitocondriais/metabolismo
Mutação
NAD/metabolismo
Biogênese de Organelas
Consumo de Oxigênio
Doença de Parkinson/genética
Proteínas Quinases/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Serina Endopeptidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HSP90 Heat-Shock Proteins); 0 (Mitochondrial Proteins); 0 (Reactive Oxygen Species); 0 (TRAP1 protein, human); 0U46U6E8UK (NAD); 8L70Q75FXE (Adenosine Triphosphate); 9100L32L2N (Metformin); EC 2.7.- (Protein Kinases); EC 2.7.11.1 (PTEN-induced putative kinase); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx202


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[PMID]:28973452
[Au] Autor:Li B; Yue Y; Yuan Z; Zhang F; Li P; Song N; Lin W; Liu Y; Yang Y; Li Z; Gu L
[Ad] Endereço:Key Laboratory of Rare and Uncommon Diseases, Department of Microbiology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China.
[Ti] Título:Salmonella STM1697 coordinates flagella biogenesis and virulence by restricting flagellar master protein FlhD4C2 from recruiting RNA polymerase.
[So] Source:Nucleic Acids Res;45(17):9976-9989, 2017 Sep 29.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Salmonella reduces flagella biogenesis to avoid detection within host cells by a largely unknown mechanism. We identified an EAL-like protein STM1697 as required and sufficient for this process. STM1697 surges to a high level after Salmonella enters host cells and restrains the expression of flagellar genes by regulating the function of flagellar switch protein FlhD4C2, the transcription activator of all other flagellar genes. Unlike other anti-FlhD4C2 factors, STM1697 does not prevent FlhD4C2 from binding to target DNA. A 2.0 Å resolution STM1697-FlhD structure reveals that STM1697 binds the same region of FlhD as STM1344, but with weaker affinity. Further experiments show that STM1697 regulates flagella biogenesis by restricting FlhD4C2 from recruiting RNA polymerase and the regulatory effect of STM1697 on flagellar biogenesis and virulence are all achieved by interaction with FlhD. Finally, we describe a novel mechanism mediated by STM1697 in which Salmonella can inhibit the production of flagella antigen and escape from the host immune system.
[Mh] Termos MeSH primário: Proteínas de Bactérias/genética
RNA Polimerases Dirigidas por DNA/genética
Flagelos/metabolismo
Regulação Bacteriana da Expressão Gênica
Genes Reguladores
Genoma Bacteriano
Salmonella typhimurium/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Proteínas de Bactérias/química
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Clonagem Molecular
RNA Polimerases Dirigidas por DNA/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
Feminino
Flagelos/ultraestrutura
Expressão Gênica
Macrófagos/microbiologia
Camundongos
Camundongos Endogâmicos BALB C
Modelos Moleculares
Biogênese de Organelas
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Estrutura Secundária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Salmonella typhimurium/metabolismo
Salmonella typhimurium/patogenicidade
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Recombinant Proteins); EC 2.7.7.6 (DNA-Directed RNA Polymerases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx656



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