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[PMID]:28463417
[Au] Autor:Tolosa L; Gómez-Lechón MJ; Donato MT
[Ad] Endereço:Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS-La Fe), Valencia, Spain.
[Ti] Título:A Multi-Parametric Fluorescent Assay for the Screening and Mechanistic Study of Drug-Induced Steatosis in Liver Cells in Culture.
[So] Source:Curr Protoc Toxicol;72:14.15.1-14.15.11, 2017 May 02.
[Is] ISSN:1934-9262
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human hepatic cells have been used for drug safety risk evaluations throughout early development phases. They provide rapid, cost-effective early feedback to identify drug candidates with potential hepatotoxicity. This unit presents a cell-based assay to evaluate the risk of liver damage associated with steatogenic drugs. Detailed protocols for cell exposure to test compounds and for the assessment of steatosis-related cell parameters (intracellular lipid content, reactive oxygen species production, mitochondrial impairment, and cell death) are provided. A few representative results that illustrate the utility of this procedure for the screening of drug-induced steatosis are shown. © 2017 by John Wiley & Sons, Inc.
[Mh] Termos MeSH primário: Fígado Gorduroso/induzido quimicamente
Fígado Gorduroso/patologia
Fígado/citologia
[Mh] Termos MeSH secundário: Morte Celular/efeitos dos fármacos
Células Cultivadas
Doença Hepática Induzida por Substâncias e Drogas
Hepatócitos/metabolismo
Seres Humanos
Metabolismo dos Lipídeos/efeitos dos fármacos
Mitocôndrias Hepáticas/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
Toxicologia/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cptx.20


  2 / 23763 MEDLINE  
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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]:29284039
[Au] Autor:Cassim S; Raymond VA; Lapierre P; Bilodeau M
[Ad] Endereço:Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
[Ti] Título:From in vivo to in vitro: Major metabolic alterations take place in hepatocytes during and following isolation.
[So] Source:PLoS One;12(12):e0190366, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The liver plays a key role in maintaining physiological homeostasis and hepatocytes are largely responsible for this. The use of isolated primary hepatocytes has become an essential tool for the study of nutrient physiology, xenobiotic metabolism and several liver pathologies. Since hepatocytes are removed from their normal environment, the isolation procedure and in vitro culture of primary hepatocytes is partially known to induce undesired metabolic changes. We aimed to perform a thorough metabolic profiling of primary cells before, during and after isolation using state-of-the-art techniques. Extensive metabolite measurements using HPLC were performed in situ in the liver, during hepatocyte isolation using the two-step collagenase perfusion method and during in vitro cell culture for up to 48 hours. Assessment of mitochondrial respiratory capacity and ATP-linked respiration of isolated primary hepatocytes was performed using extracellular flux analysis. Primary hepatocytes displayed a drastic decrease in antioxidative-related metabolites (NADPH, NADP, GSH and GSSG) during the isolation procedure when compared to the in situ liver (P<0.001). Parallel assessment of citric acid cycle activity showed a significant decrease of up to 95% in Acetyl-CoA, Isocitrate/Citrate ratio, Succinate, Fumarate and Malate in comparison to the in situ liver (P<0.001). While the levels of several cellular energetic metabolites such as Adenosine, AMP, ADP and ATP were found to be progressively reduced during the isolation procedure and cell culture (P<0.001), higher ATP/ADP ratio and energy charge level were observed when primary cells were cultured in vitro compared to the in situ liver (P<0.05). In addition, a significant decrease in the respiratory capacity occurred after 24 hours in culture. Interestingly, this was not associated with a significant modification of ATP-linked respiration. In conclusion, major metabolic alterations occur immediately after hepatocytes are removed from the liver. These changes persist or increase during in vitro culture. These observations need to be taken into account when using primary hepatocytes for the study of metabolism or liver physiopathology.
[Mh] Termos MeSH primário: Hepatócitos/metabolismo
[Mh] Termos MeSH secundário: Animais
Antioxidantes/metabolismo
Cromatografia Líquida de Alta Pressão
Ciclo do Ácido Cítrico
Técnicas In Vitro
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Mitocôndrias Hepáticas/metabolismo
Estresse Oxidativo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antioxidants)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171229
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190366


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[PMID]:29196105
[Au] Autor:Lu Y; Kan H; Wang Y; Wang D; Wang X; Gao J; Zhu L
[Ad] Endereço:Institute of Nautical Medicine, Nantong University, Nantong 226019, China.
[Ti] Título:Asiatic acid ameliorates hepatic ischemia/reperfusion injury in rats via mitochondria-targeted protective mechanism.
[So] Source:Toxicol Appl Pharmacol;338:214-223, 2018 01 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It has been proved that asiatic acid (AA) directly targets mitochondria and acts as a mild mitochondrial uncoupler. In this study, we aim to investigate the protective effects of AA against ischemia/reperfusion (I/R)-induced liver injury in rats and some underlying mechanisms involved were elucidated. The results showed that 50mg/kg AA pre-treatment significantly reduced I/R-induced liver damage, characterized by the decreased release of aspartate aminotransferase (AST) and TNF-α. Furthermore, AA pre-treatment dramatically inhibited the production of MDA and increased the hepatic SOD, catalase activities and GSH levels in liver tissue of I/R rats which indicated that AA ameliorated I/R-induced liver damage by reducing oxidative stress. In isolated liver mitochondria in I/R rats, AA improved mitochondrial respiration, decreased mitochondrial MDA level, prevented I/R-induced drop of mitochondrial membrane potential (MMP) and increased ATP content, indicating the protective effect of AA against I/R-induced mitochondrial oxidative damage. In isolated liver mitochondria from normal rats, AA was found to effectively block succinate-driven H O production no matter of the presence or absence of rotenone. In addition, AA showed a clear protective effect against anoxia/reoxygenation (A/R)-induced injury in isolated rat liver mitochondria when malate/glutamate were used as respiratory substrates. After AA treatment, mitochondrial respiratory dysfunction induced by A/R was ameliorated. Also, A/R-induced mitochondrial ROS generation was significantly inhibited by AA. In conclusion, AA can attenuate I/R-induced liver damage in rats and A/R-induced mitochondrial injury in isolated rat liver mitochondria by inhibiting oxidative stress and restoring mitochondrial function. Therefore, AA might have potential as a mitochondrial protective agent for use in clinical treatment of hepatic I/R injury.
[Mh] Termos MeSH primário: Fígado/irrigação sanguínea
Mitocôndrias Hepáticas/efeitos dos fármacos
Triterpenos Pentacíclicos/farmacologia
Traumatismo por Reperfusão/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Masculino
Malondialdeído/análise
Triterpenos Pentacíclicos/uso terapêutico
Ratos
Ratos Sprague-Dawley
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pentacyclic Triterpenes); 0 (Reactive Oxygen Species); 4Y8F71G49Q (Malondialdehyde); 9PA5A687X5 (asiatic acid)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE


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[PMID]:29223393
[Au] Autor:Korotkov SM; Konovalova SA; Nesterov VP; Brailovskaya IV
[Ad] Endereço:Sechenov Institute of Evolutionary Physiology and Biochemistry, The Russian Academy of Sciences, Thorez pr. 44, 194223 St. Petersburg, Russia. Electronic address: korotkov@SK1645.spb.edu.
[Ti] Título:Mersalyl prevents the Tl -induced permeability transition pore opening in the inner membrane of Ca -loaded rat liver mitochondria.
[So] Source:Biochem Biophys Res Commun;495(2):1716-1721, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It was earlier shown that the calcium load of rat liver mitochondria in medium containing TlNO and KNO resulted in the Tl -induced mitochondrial permeability transition pore (MPTP) opening in the inner membrane. This opening was accompanied by an increase in swelling and membrane potential dissipation and a decrease in state 3, state 4, and 2,4-dinitrophenol-uncoupled respiration. This respiratory decrease was markedly leveled by mersalyl (MSL), the phosphate symporter (PiC) inhibitor which poorly stimulated the calcium-induced swelling, but further increased the potential dissipation. All of these effects of Ca and MSL were visibly reduced in the presence of the MPTP inhibitors (ADP, N-ethylmaleimide, and cyclosporine A). High MSL concentrations attenuated the ability of ADP to inhibit the MPTP. Our data suggest that the PiC can participate in the Tl -induced MPTP opening in the inner membrane of Ca -loaded rat liver mitochondria.
[Mh] Termos MeSH primário: Mersalil/farmacologia
Mitocôndrias Hepáticas/efeitos dos fármacos
Mitocôndrias Hepáticas/metabolismo
Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos
Proteínas de Transporte da Membrana Mitocondrial/metabolismo
Tálio/farmacologia
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Técnicas In Vitro
Transporte de Íons/efeitos dos fármacos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Membranas Mitocondriais/efeitos dos fármacos
Membranas Mitocondriais/metabolismo
Dilatação Mitocondrial/efeitos dos fármacos
Consumo de Oxigênio/efeitos dos fármacos
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Mitochondrial Membrane Transport Proteins); 0 (mitochondrial permeability transition pore); 5X1IO031V8 (Mersalyl); AD84R52XLF (Thallium); SY7Q814VUP (Calcium)
[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:171211
[St] Status:MEDLINE


  6 / 23763 MEDLINE  
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[PMID]:29363934
[Au] Autor:Voloshchuk ON; Kopylchuk GP
[Ti] Título:The ratio of ubiqiunon redox forms in the liver mitochondria under toxic hepatitis induced on the background of alimentary protein deficiency.
[So] Source:Vopr Pitan;84(5):82-7, 2015.
[Is] ISSN:0042-8833
[Cp] País de publicação:Russia (Federation)
[La] Idioma:eng
[Ab] Resumo:The level of the total ubiqiunon and redox forms CoQ in the rat liver mitochondria under the conditions of alimentary protein deficiency and toxic hepatitis, induced on the background protein deficiency has been investigated. Research has been carried out on 36 white non-linear rats, divided into 4 groups: 1 ­ rats, maintained on the complete semisynthetic ration; 2 ­ rats, fed low-protein ration; 3 ­ rats with acute acetaminophen-induced hepatitis, maintained on complete ration; 4 ­ rats with acetaminophen-induced hepatitis, maintained under the conditions of protein deficiency. The content of total and oxidized ubiqiunon was determined spectrophotometrically at λ=275 nm (molar extinction coefficient 12.25 Mm-1×sm-1). Reduced ubiqiunon content was determined by the difference between total and oxidized ubiqiunon content. The amount of tyrosine in the liver was measured in deproteinised by 6% sulfosalicylic acid extracts of liver tissue on an automated amino acid analyzer. The decrease of the total ubiqiunon content in liver mitochondria by 35% on the background of 2-fold decrease of oxidized ubiqiunon and preservation of reduced ubiqiunon amount has been estimated under the conditions of low-protein diet. Simultaneously the 5-fold decrease of liver content of tyrosine ­ the ubiqiunon precursor ­ has been observed. It has been shown, that under the conditions of acetaminophen-induced hepatitis the content of total ubiqiunon and its redox forms in the liver mitochondria of rats fed complete diet didn't change significantly comparing to control. A decrease of total ubiqiunon by 60% on the background of acute (18-fold) decrease of reduced ubiqiunon in liver mitochondria of rats with hepatitis, fed low-protein diet, has been observed. Established changes of the content of redox ubiquinone forms (a key component of the oxidative phosphorylation system in the liver mitochondria) can be considered as one of the mechanisms of malfunction of energy biotransformation system under the conditions of toxic liver injury in animals with protein deficiency.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Mitocôndrias Hepáticas/metabolismo
Fosforilação Oxidativa
Deficiência de Proteína/metabolismo
Ubiquinona/metabolismo
[Mh] Termos MeSH secundário: Acetaminofen/efeitos adversos
Acetaminofen/farmacologia
Animais
Doença Hepática Induzida por Substâncias e Drogas/patologia
Masculino
Mitocôndrias Hepáticas/patologia
Oxirredução/efeitos dos fármacos
Deficiência de Proteína/patologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
1339-63-5 (Ubiquinone); 362O9ITL9D (Acetaminophen)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE


  7 / 23763 MEDLINE  
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[PMID]:29227606
[Au] Autor:Kopylchuk GP; Voloshchuk OM
[Ti] Título:Peculiarities of the free radical processes in rat liver mitochondria under toxic hepatitis on the background of alimentary protein deficiency.
[So] Source:Ukr Biochem J;88(2):66-72, 2016 Mar-Apr.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:The rate of superoxide anion radical, hydroxyl radical and hydrogen peroxide generation, the level of oxidative modification of mitochondrial proteins in the liver of rats with toxic hepatitis was investigated on the background of alimentary protein deficiency. We did not find significant increases of the intensity of free radical processes in liver mitochondria of rats maintained on the protein-deficient ration. The most significant intensification of free radical processes in liver mitochondria is observed under the conditions of toxic hepatitis, induced on the background of alimentary protein deprivation. Under these conditions the aggravation of all studied forms of reactive oxygen species generation was observed in liver mitochondria. The generation rates were increased as follows: O2 ­ by 1.7 times, Н2О2 ­ by 1.5 times, •ОН ­ practically double on the background of accumulation of oxidized mitochondria-derived proteins. The established changes in thiol groups' redox status of respiratory chain proteins insoluble in 0.05 M sodium-phosphate buffer (pH 11.5), and changes of their carbonyl derivatives content may be considered as one of the regulatory factors of mitochondrial energy-generating function.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Peróxido de Hidrogênio/metabolismo
Radical Hidroxila/metabolismo
Mitocôndrias Hepáticas/metabolismo
Deficiência de Proteína/metabolismo
Superóxidos/metabolismo
[Mh] Termos MeSH secundário: Acetaminofen/toxicidade
Animais
Animais não Endogâmicos
Doença Hepática Induzida por Substâncias e Drogas/complicações
Doença Hepática Induzida por Substâncias e Drogas/patologia
Dieta com Restrição de Proteínas/efeitos adversos
Peróxido de Hidrogênio/agonistas
Radical Hidroxila/agonistas
Fígado/efeitos dos fármacos
Fígado/metabolismo
Fígado/patologia
Mitocôndrias Hepáticas/efeitos dos fármacos
Oxirredução
Estresse Oxidativo
Carbonilação Proteica
Deficiência de Proteína/complicações
Deficiência de Proteína/etiologia
Deficiência de Proteína/patologia
Ratos
Superóxidos/agonistas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
11062-77-4 (Superoxides); 3352-57-6 (Hydroxyl Radical); 362O9ITL9D (Acetaminophen); BBX060AN9V (Hydrogen Peroxide)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.02.066


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[PMID]:28457421
[Au] Autor:de Lourdes Jorge G; Dos Reis Tártaro R; Fazzio Escanhoela CA; Boin IFSF
[Ad] Endereço:Hepatic Surgical Laboratory, Nucleus of Medicine and Experimental Surgery, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
[Ti] Título:Later Evaluation of Ischemia and Reperfusion by the Pringle Maneuver in Wistar Rats, Demonstrating That Hepatic Lesions Can Be Reversible.
[So] Source:Transplant Proc;49(4):898-901, 2017 May.
[Is] ISSN:1873-2623
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: There has been much research on hepatic ischemia and reperfusion by means of short or longer interruption of the portal triad. The aim of this work was to evaluate the mitochondrial respiratory activity and liver histology at 2 different times after the Pringle maneuver. METHODS: Twenty-eight male Wistar rats, weighing ∼308 g, with histologic and mitochondrial study: immediate ischemic group (IIG; 40 minutes; 9 animals) and late ischemic group (LIG; 28 days; 9 animals). The rats were anesthetized and underwent a U-incision in the abdomen. In a simulated operation, manipulation of the hepatic pedicle was performed (5 animals immediate [ISG] and 5 late [LSG]). The hepatic pedicle was clamped for 20 minutes of ischemia foloowed by 20 minutes of reperfusion. The animals were killed under anesthesia. RESULTS: Mitochondria when stimulated by adenosine diphosphate or carbonylcyanide p-trifluoromethoxyphenylhydrazone had a significant respiratory reduction (P < .001). The respiratory control ratio in the LIG was altered (P < .02) compared with IIG. In the resting state, there was no change in the velocity of respiration between ischemic groups. Histopathologic findings showed 55.5% sinusoidal dilatation in IIG and 66.6% in LIG; 77.7% ballooning in IIG and 55.5% in LIG; and 11.1% focal necrosis in both IIG and LIG. CONCLUSIONS: The oxidative phosphorylation system recovered with improvement in mitochondrial respiration; however, morphologic recovery was associated with the type and intensity of injury.
[Mh] Termos MeSH primário: Hemostasia Cirúrgica/efeitos adversos
Isquemia/patologia
Hepatopatias/patologia
Mitocôndrias Hepáticas/metabolismo
Traumatismo por Reperfusão/patologia
Reperfusão/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Hemostasia Cirúrgica/métodos
Isquemia/etiologia
Fígado/patologia
Circulação Hepática
Hepatopatias/etiologia
Masculino
Mitocôndrias Hepáticas/efeitos dos fármacos
Sistema Porta
Ratos
Ratos Wistar
Reperfusão/métodos
Traumatismo por Reperfusão/etiologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:28458255
[Au] Autor:Zhang Y; Bharathi SS; Rardin MJ; Lu J; Maringer KV; Sims-Lucas S; Prochownik EV; Gibson BW; Goetzman ES
[Ad] Endereço:From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
[Ti] Título:Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain.
[So] Source:J Biol Chem;292(24):10239-10249, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. Here, SIRT5 was observed to bind to cardiolipin via an amphipathic helix on its N terminus. , succinyl-CoA was used to succinylate liver mitochondrial membrane proteins. SIRT5 largely reversed the succinyl-CoA-driven lysine succinylation. Quantitative mass spectrometry of SIRT5-treated membrane proteins pointed to the electron transport chain, particularly Complex I, as being highly targeted for desuccinylation by SIRT5. Correspondingly, SIRT5 HEK293 cells showed defects in both Complex I- and Complex II-driven respiration. In mouse liver, SIRT5 expression was observed to localize strictly to the periportal hepatocytes. However, homogenates prepared from whole SIRT5 liver did show reduced Complex II-driven respiration. The enzymatic activities of Complex II and ATP synthase were also significantly reduced. Three-dimensional modeling of Complex II suggested that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. We postulate that succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. Lastly, SIRT5 mice, like humans with Complex II deficiency, were found to have mild lactic acidosis. Our findings suggest that SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function.
[Mh] Termos MeSH primário: Cardiolipinas/metabolismo
Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo
Hepatócitos/enzimologia
Modelos Moleculares
Processamento de Proteína Pós-Traducional
Sirtuínas/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Cardiolipinas/química
Complexo I de Transporte de Elétrons/metabolismo
Complexo II de Transporte de Elétrons/metabolismo
Células HEK293
Hepatócitos/metabolismo
Seres Humanos
Lisina/metabolismo
Camundongos
Camundongos Knockout
Mitocôndrias Hepáticas/enzimologia
Mitocôndrias Hepáticas/metabolismo
Membranas Mitocondriais/enzimologia
Membranas Mitocondriais/metabolismo
Mutação
Transporte Proteico
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sirtuínas/química
Sirtuínas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cardiolipins); 0 (Electron Transport Chain Complex Proteins); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (SIRT5 protein, mouse); EC 1.3.5.1 (Electron Transport Complex II); EC 1.6.5.3 (Electron Transport Complex I); EC 3.5.1.- (SIRT5 protein, human); EC 3.5.1.- (Sirtuins); K3Z4F929H6 (Lysine)
[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:170502
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.785022


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[PMID]:29252954
[Au] Autor:Vollmer JP; Haen S; Wolburg H; Lehmann R; Steiner J; Reddersen S; Fend F; Fallier-Becker P
[Ad] Endereço:Institute of Anaesthesiology, Klinikum Stuttgart, Germany.
[Ti] Título:Propofol Related Infusion Syndrome: Ultrastructural Evidence for a Mitochondrial Disorder.
[So] Source:Crit Care Med;46(1):e91-e94, 2018 Jan.
[Is] ISSN:1530-0293
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The objective of this report of a fatal propofol-related infusion syndrome in a young adult was to present-to our knowledge for the first time-direct ultrastructural evidence for the central role of mitochondrial damage in the pathogenesis of this syndrome. DATA SOURCES: Histological and electron microscopical analysis of liver, skeletal, and heart muscle obtained by autopsy and blood obtained from patient. STUDY SELECTION: Case report. DATA EXTRACTION: In addition to conventional macroscopical and histological investigations, electron-microscopical analysis of myocardial- and skeletal muscle and liver tissue obtained at autopsy from a young man was performed in order to search for ultrastructural changes of mitochondria. Acylcarnitine concentrations of his blood were determined by ultra-high performance liquid chromatography mass spectrometry. DATA SYNTHESIS: A 19-year-old male was admitted with acute left-side hemiparesis. The patient was intubated, then propofol infusion started, and a craniotomy was performed to remove an intracerebral hematoma. In the postoperative period, the patient presented with elevated intracranial pressure and brain edema. After repeat surgery, the patient showed impaired systolic left ventricular function, increasing fever, anuria, hyperkalemia, and metabolic acidosis, and he finally expired. Electron microscopy revealed dark, electron dense amorphous structures associated with mitochondria in heart muscle and liver tissue obtained at autopsy. Peripheral blood analysis revealed increased levels of acetyl-, propionyl-, butyryl-, malonyl-, and valeryl-carnitine as an indicator for propofol-related infusion syndrome, as well as for propofol-mediated inhibition of free fatty acid uptake into mitochondria, affecting beta-oxidation. CONCLUSIONS: Electron dense bodies found in association with mitochondria in muscle and liver cells probably correspond to accumulation of free fatty acid provide direct morphological evidence for the mitochondrial damage in propofol-related infusion syndrome.
[Mh] Termos MeSH primário: Doenças Mitocondriais/induzido quimicamente
Doenças Mitocondriais/patologia
Síndrome da Infusão de Propofol/patologia
[Mh] Termos MeSH secundário: Carnitina/análogos & derivados
Carnitina/sangue
Craniotomia
Hematoma Subdural Intracraniano/cirurgia
Seres Humanos
Infusões Intravenosas
Masculino
Microscopia Eletrônica
Mitocôndrias Cardíacas/efeitos dos fármacos
Mitocôndrias Cardíacas/patologia
Mitocôndrias Hepáticas/efeitos dos fármacos
Mitocôndrias Hepáticas/patologia
Mitocôndrias Musculares/efeitos dos fármacos
Mitocôndrias Musculares/patologia
Complicações Pós-Operatórias/induzido quimicamente
Complicações Pós-Operatórias/patologia
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (acylcarnitine); S7UI8SM58A (Carnitine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1097/CCM.0000000000002802



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