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[PMID]: 29241732 [Au] Autor: Park YS; Choi SE; Koh HC [Ad] Endereço: Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea. [Ti] Título: PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. [So] Source: Toxicol Lett;284:120-128, 2018 Mar 01. [Is] ISSN: 1879-3169 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Mitochondrial dynamics and mitophagy are critical processes for regulating mitochondrial homeostasis. Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial protein that plays crucial roles in apoptosis and necroptosis, but the roles of PGAM5 in mitochondrial dynamics and mitophagy remain unclear. In this study, we investigated the role of PGAM5 in carbonyl cyanide m-chlorophenylhydrazone (CCCP)-induced mitochondrial damage and the correlation between mitochondrial dynamics and mitophagy using SH-SY5Y cells. We found that CCCP decreased mitochondrial membrane potential, resulting in mitochondrial dysfunction. CCCP increased PGAM5, dynamin-related protein 1 (DRP1), and optic atrophy 1 (OPA1) expression of the mitochondrial fraction in a time-dependent manner. Knockdown of PGAM5 inhibited DRP1 translocation without a change in OPA1 expression in CCCP-treated cells. Furthermore, knockdown of PGAM5 and DRP1 significantly blocked the increase of PTEN-induced putative protein kinase 1 (PINK1) and Parkin expression in the mitochondrial fraction of CCCP-treated cells. Interestingly, CCCP did not alter PINK1/Parkin expression in the mitochondrial fraction of OPA1 knockdown cells. Inhibiting mitophagy by PGAM5 knockdown accelerated CCCP-induced apoptosis. CCCP treatment also results in PINK1 stabilization on the mitochondrial membrane, which subsequently increases Parkin recruitment from the cytosol to abnormal mitochondria. In addition, we found that CCCP increased the level of mitochondrial LC3II, indicating that Parkin recruitment of PINK1 is a result of mitophagy. We propose that activation of PGAM5 is associated with DRP1 recruitment and PINK1 stabilization, which contribute to the modulation of mitophagy in CCCP-treated cells with mitochondrial dysfunction. In conclusion, we demonstrated that PGAM5 regulates PINK1-Parkin-mediated mitophagy, which can exert a neuroprotective effect against CCCP-induced apoptosis. [Mh] Termos MeSH primário: Carbonil Cianeto m-Clorofenil Hidrazona/toxicidade GTP Fosfo-Hidrolases/metabolismo Proteínas Associadas aos Microtúbulos/metabolismo Degradação Mitocondrial/efeitos dos fármacos Proteínas Mitocondriais/metabolismo Fosfoproteínas Fosfatases/metabolismo Proteínas Quinases/metabolismo Ubiquitina-Proteína Ligases/metabolismo [Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos Linhagem Celular Tumoral GTP Fosfo-Hidrolases/genética Técnicas de Silenciamento de Genes Seres Humanos Potencial da Membrana Mitocondrial/efeitos dos fármacos Proteínas Associadas aos Microtúbulos/genética Mitocôndrias/efeitos dos fármacos Mitocôndrias/metabolismo Mitocôndrias/patologia Proteínas Mitocondriais/genética Fosfoproteínas Fosfatases/genética Proteínas Quinases/genética Ubiquitina-Proteína Ligases/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Microtubule-Associated Proteins); 0 (Mitochondrial Proteins); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.3.2.27 (parkin protein); EC 2.7.- (Protein Kinases); EC 2.7.11.1 (PTEN-induced putative kinase); EC 3.1.3.16 (PGAM5 protein, human); EC 3.1.3.16 (Phosphoprotein Phosphatases); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.5.5 (DNM1L protein, human) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180221 [Lr] Data última revisão: 180221 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171216 [St] Status: MEDLINE

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[PMID]: 29227076 [Au] Autor: Danylovych HV [Ti] Título: Evaluation of functioning of mitochondrial electron transport chain with NADH and FAD autofluorescence [So] Source: Ukr Biochem J;88(1):31-43, 2016 Jan-Feb. [Is] ISSN: 2409-4943 [Cp] País de publicação: Ukraine [La] Idioma: eng [Ab] Resumo: We prove the feasibility of evaluation of mitochondrial electron transport chain function in isolated mitochondria of smooth muscle cells of rats from uterus using fluorescence of NADH and FAD coenzymes. We found the inversely directed changes in FAD and NADH fluorescence intensity under normal functioning of mitochondrial electron transport chain. The targeted effect of inhibitors of complex I, III and IV changed fluorescence of adenine nucleotides. Rotenone (5 µM) induced rapid increase in NADH fluorescence due to inhibition of complex I, without changing in dynamics of FAD fluorescence increase. Antimycin A, a complex III inhibitor, in concentration of 1 µg/ml caused sharp increase in NADH fluorescence and moderate increase in FAD fluorescence in comparison to control. NaN3 (5 mM), a complex IV inhibitor, and CCCP (10 µM), a protonophore, caused decrease in NADH and FAD fluorescence. Moreover, all the inhibitors caused mitochondria swelling. NO donors, e.g. 0.1 mM sodium nitroprusside and sodium nitrite similarly to the effects of sodium azide. Energy-dependent Ca2+ accumulation in mitochondrial matrix (in presence of oxidation substrates and Mg-ATP2- complex) is associated with pronounced drop in NADH and FAD fluorescence followed by increased fluorescence of adenine nucleotides, which may be primarily due to Ca2+- dependent activation of dehydrogenases of citric acid cycle. Therefore, the fluorescent signal of FAD and NADH indicates changes in oxidation state of these nucleotides in isolated mitochondria, which may be used to assay the potential of effectors of electron transport chain. [Mh] Termos MeSH primário: Complexo III da Cadeia de Transporte de Elétrons/metabolismo Complexo IV da Cadeia de Transporte de Elétrons/metabolismo Complexo I de Transporte de Elétrons/metabolismo Flavina-Adenina Dinucleotídeo/química Mitocôndrias/metabolismo NAD/química [Mh] Termos MeSH secundário: Animais Antimicina A/farmacologia Cálcio/metabolismo Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Fracionamento Celular Transporte de Elétrons/efeitos dos fármacos Complexo I de Transporte de Elétrons/antagonistas & inibidores Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores Inibidores Enzimáticos/farmacologia Feminino Flavina-Adenina Dinucleotídeo/metabolismo Mitocôndrias/efeitos dos fármacos Miócitos de Músculo Liso/efeitos dos fármacos Miócitos de Músculo Liso/metabolismo Miométrio/efeitos dos fármacos Miométrio/metabolismo NAD/metabolismo Nitroprussiato/farmacologia Imagem Óptica Ratos Rotenona/farmacologia Azida Sódica/farmacologia Nitrito de Sódio/farmacologia Desacopladores/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enzyme Inhibitors); 0 (Uncoupling Agents); 03L9OT429T (Rotenone); 0U46U6E8UK (NAD); 146-14-5 (Flavin-Adenine Dinucleotide); 169D1260KM (Nitroprusside); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); 642-15-9 (Antimycin A); 968JJ8C9DV (Sodium Azide); EC 1.10.2.2 (Electron Transport Complex III); EC 1.6.5.3 (Electron Transport Complex I); EC 1.9.3.1 (Electron Transport Complex IV); M0KG633D4F (Sodium Nitrite); SY7Q814VUP (Calcium) [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/ubj88.01.031

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[PMID]: 29182624 [Au] Autor: Kansaku K; Takeo S; Itami N; Kin A; Shirasuna K; Kuwayama T; Iwata H [Ad] Endereço: Department of Animal Science, Tokyo University of Agriculture, Atsugi City, Kanagawa, Japan. [Ti] Título: Maternal aging affects oocyte resilience to carbonyl cyanide-m-chlorophenylhydrazone -induced mitochondrial dysfunction in cows. [So] Source: PLoS One;12(11):e0188099, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Mitochondrial quality control is important for maintaining cellular and oocyte viability. In addition, aging affects mitochondrial quality in many cell types. In the present study, we examined how aging affects oocyte mitochondrial biogenesis and degeneration in response to induced mitochondrial dysfunction. Cumulus oocyte complexes were harvested from the ovaries of young (21‒45 months) and aged (≥120 months) cows and treated for 2 hours with 10 µM carbonyl cyanide-m- chlorophenylhydrazone (CCCP), or a vehicle control, after which cumulus oocyte complexes were subjected to in vitro fertilization and culture. CCCP treatment reduced ATP content and increased reactive oxygen species (ROS) levels in the oocytes of both young and aged cows. When CCCP-treated cumulus oocyte complexes were subsequently cultured for 19 hours and/or subjected to fertilization, high ROS levels in oocytes and a low rate of blastocyst development was observed in oocytes derived from aged cows. In addition, we observed differential responses in mitochondrial biogenesis to CCCP treatment between young and aged cows. CCCP treatment enhanced mitochondrial biogenesis concomitant with upregulation of SIRT1 expression in oocytes of young, but not aged, cows. In conclusion, aging affects mitochondrial quality control and recuperation of oocytes following CCCP-induced mitochondrial dysfunction. [Mh] Termos MeSH primário: Envelhecimento/metabolismo Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Mitocôndrias/efeitos dos fármacos Oócitos/efeitos dos fármacos [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Animais Bovinos Feminino Leupeptinas/farmacologia Mitocôndrias/fisiologia Oócitos/citologia Oócitos/metabolismo Espécies Reativas de Oxigênio/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Leupeptins); 0 (Reactive Oxygen Species); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); 8L70Q75FXE (Adenosine Triphosphate); RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171226 [Lr] Data última revisão: 171226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171129 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0188099

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[PMID]: 28058736 [Au] Autor: Losano J; Angrimani D; Dalmazzo A; Rui BR; Brito MM; Mendes CM; Kawai G; Vannucchi CI; Assumpção M; Barnabe VH; Nichi M [Ad] Endereço: Department of Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, SP, Brazil. [Ti] Título: Effect of mitochondrial uncoupling and glycolysis inhibition on ram sperm functionality. [So] Source: Reprod Domest Anim;52(2):289-297, 2017 Apr. [Is] ISSN: 1439-0531 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Studies have demonstrated the importance of mitochondria to sperm functionality, as the main source of ATP for cellular homoeostasis and motility. However, the role of mitochondria on sperm metabolism is still controversial. Studies indicate that, for some species, glycolysis may be the main mechanism for sperm energy production. For ram sperm, such pathway is not clear. Thus, we evaluated ram sperm in response to mitochondrial uncoupling and glycolysis inhibition aiming to assess the importance of each pathway for sperm functionality. Statistical analysis was performed by the SAS System for Windows, using the General Linear Model Procedure. Data were tested for residue normality and variance homogeneity. A p < .05 was considered significant. Groups treated with the mitochondrial uncoupler Carbonyl cyanide 3 chlorophenylhydrazone (CCCP) showed a decrease in the percentage of cells with low mitochondrial activity and high mitochondrial membrane potential. We also observed that the highest CCCP concentration promotes a decrease in sperm susceptibility to lipid peroxidation. Regardless the lack of effect of CCCP on total motility, this substance induced significant alterations on sperm kinetics. Besides the interference of CCCP on spermatic movement patterns, it was also possible to observe such an effect in samples treated with the inhibitor of glycolysis (2-deoxy-d-glucose, DOG). Furthermore, treatment with DOG also led to a dose-dependent increase in sperm susceptibility to lipid peroxidation. Based on our results, we suggest that the glycolysis appears to be as important as oxidative phosphorylation for ovine sperm kinetics as this mechanism is capable of maintaining full motility when most of the cells have a low mitochondrial membrane potential. Furthermore, we found that changes in the glycolytic pathway trough glycolysis inhibition are likely involved in mitochondrial dysfunction and sperm oxidative unbalance. [Mh] Termos MeSH primário: Mitocôndrias/fisiologia Ovinos/fisiologia Espermatozoides/fisiologia [Mh] Termos MeSH secundário: Animais Carbonil Cianeto m-Clorofenil Hidrazona/análogos & derivados Glicólise Seres Humanos Masculino Potencial da Membrana Mitocondrial/efeitos dos fármacos Potencial da Membrana Mitocondrial/fisiologia Estresse Oxidativo Espermatozoides/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); 946-76-9 (carbonylcyanide 4-chlorophenylhydrazone) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170901 [Lr] Data última revisão: 170901 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170107 [St] Status: MEDLINE [do] DOI: 10.1111/rda.12901

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[PMID]: 27858084 [Au] Autor: Jones E; Gaytan N; Garcia I; Herrera A; Ramos M; Agarwala D; Rana M; Innis-Whitehouse W; Schuenzel E; Gilkerson R [Ad] Endereço: Department of Biology, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX, 78539-2999, USA. [Ti] Título: A threshold of transmembrane potential is required for mitochondrial dynamic balance mediated by DRP1 and OMA1. [So] Source: Cell Mol Life Sci;74(7):1347-1363, 2017 Apr. [Is] ISSN: 1420-9071 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: As an organellar network, mitochondria dynamically regulate their organization via opposing fusion and fission pathways to maintain bioenergetic homeostasis and contribute to key cellular pathways. This dynamic balance is directly linked to bioenergetic function: loss of transmembrane potential across the inner membrane (Δψ ) disrupts mitochondrial fission/fusion balance, causing fragmentation of the network. However, the level of Δψ required for mitochondrial dynamic balance, as well as the relative contributions of fission and fusion pathways, have remained unclear. To explore this, mitochondrial morphology and Δψ were examined via confocal imaging and tetramethyl rhodamine ester (TMRE) flow cytometry, respectively, in cultured 143B osteosarcoma cells. When normalized to the TMRE value of untreated 143B cells as 100%, both genetic (mtDNA-depleted ρ ) and pharmacological [carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated] cell models below 34% TMRE fluorescence were unable to maintain mitochondrial interconnection, correlating with loss of fusion-active long OPA1 isoforms (L-OPA1). Mechanistically, this threshold is maintained by mechanistic coordination of DRP1-mediated fission and OPA1-mediated fusion: cells lacking either DRP1 or the OMA1 metalloprotease were insensitive to loss of Δψ , instead maintaining an obligately fused morphology. Collectively, these findings demonstrate a mitochondrial 'tipping point' threshold mediated by the interaction of Δψ with both DRP1 and OMA1; moreover, DRP1 appears to be required for effective OPA1 maintenance and processing, consistent with growing evidence for direct interaction of fission and fusion pathways. These results suggest that Δψ below threshold coordinately activates both DRP1-mediated fission and OMA1 cleavage of OPA1, collapsing mitochondrial dynamic balance, with major implications for a range of signaling pathways and cellular life/death events. [Mh] Termos MeSH primário: GTP Fosfo-Hidrolases/metabolismo Metaloproteases/metabolismo Proteínas Associadas aos Microtúbulos/metabolismo Mitocôndrias/fisiologia Dinâmica Mitocondrial Proteínas Mitocondriais/metabolismo [Mh] Termos MeSH secundário: Animais Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Linhagem Celular Tumoral DNA Mitocondrial/genética DNA Mitocondrial/metabolismo GTP Fosfo-Hidrolases/deficiência GTP Fosfo-Hidrolases/genética Células HCT116 Seres Humanos Potenciais da Membrana/efeitos dos fármacos Metaloproteases/deficiência Metaloproteases/genética Camundongos Knockout Microscopia de Fluorescência Proteínas Associadas aos Microtúbulos/deficiência Proteínas Associadas aos Microtúbulos/genética Mitocôndrias/química Mitocôndrias/genética Dinâmica Mitocondrial/efeitos dos fármacos Proteínas Mitocondriais/deficiência Proteínas Mitocondriais/genética Reação em Cadeia da Polimerase [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA, Mitochondrial); 0 (Microtubule-Associated Proteins); 0 (Mitochondrial Proteins); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); EC 3.4.- (Metalloproteases); EC 3.4.- (OMA1 protein, mouse); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.5.5 (DNM1L protein, human) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170910 [Lr] Data última revisão: 170910 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161119 [St] Status: MEDLINE [do] DOI: 10.1007/s00018-016-2421-9

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[PMID]: 27381181 [Au] Autor: Tahrir FG; Knezevic T; Gupta MK; Gordon J; Cheung JY; Feldman AM; Khalili K [Ad] Endereço: Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania. [Ti] Título: Evidence for the Role of BAG3 in Mitochondrial Quality Control in Cardiomyocytes. [So] Source: J Cell Physiol;232(4):797-805, 2017 Apr. [Is] ISSN: 1097-4652 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Mitochondrial abnormalities impact the development of myofibrillar myopathies. Therefore, understanding the mechanisms underlying the removal of dysfunctional mitochondria from cells is of great importance toward understanding the molecular events involved in the genesis of cardiomyopathy. Earlier studies have ascribed a role for BAG3 in the development of cardiomyopathy in experimental animals leading to the identification of BAG3 mutations in patients with heart failure which may play a part in the onset of disease development and progression. BAG3 is co-chaperone of heat shock protein 70 (HSP70), which has been shown to modulate apoptosis and autophagy, in several cell models. In this study, we explore the potential role of BAG3 in mitochondrial quality control. We demonstrate that siRNA mediated suppression of BAG3 production in neonatal rat ventricular cardiomyocytes (NRVCs) significantly elevates the level of Parkin, a key component of mitophagy. We found that both BAG3 and Parkin are recruited to depolarized mitochondria and promote mitophagy. Suppression of BAG3 in NRVCs significantly reduces autophagy flux and eliminates clearance of Tom20, an essential import receptor for mitochondria proteins, after induction of mitophagy. These observations suggest that BAG3 is critical for the maintenance of mitochondrial homeostasis under stress conditions, and disruptions in BAG3 expression impact cardiomyocyte function. J. Cell. Physiol. 232: 797-805, 2017. © 2016 Wiley Periodicals, Inc. [Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo Proteínas Reguladoras de Apoptose/metabolismo Mitocôndrias/metabolismo Miócitos Cardíacos/metabolismo [Mh] Termos MeSH secundário: Animais Apoptose/efeitos dos fármacos Autofagia/efeitos dos fármacos Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Linhagem Celular Metabolismo Energético Técnicas de Silenciamento de Genes Seres Humanos Lisossomos/efeitos dos fármacos Lisossomos/metabolismo Potencial da Membrana Mitocondrial/efeitos dos fármacos Mitocôndrias/efeitos dos fármacos Degradação Mitocondrial/efeitos dos fármacos Miócitos Cardíacos/efeitos dos fármacos Inibidores de Proteassoma/farmacologia Transporte Proteico/efeitos dos fármacos Ratos Sprague-Dawley Ubiquitina-Proteína Ligases/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (Apoptosis Regulatory Proteins); 0 (BAG3 protein, rat); 0 (Proteasome Inhibitors); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.3.2.27 (parkin protein) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 171102 [Lr] Data última revisão: 171102 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160707 [St] Status: MEDLINE [do] DOI: 10.1002/jcp.25476

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[PMID]: 28853780 [Ti] Título: [In process]. [So] Source: Mikrobiologiia;85(4):481-483, 2016 Jul. [Is] ISSN: 0026-3656 [Cp] País de publicação: Russia (Federation) [La] Idioma: eng [Mh] Termos MeSH primário: Biofilmes/efeitos dos fármacos Ionóforos/farmacologia Força Próton-Motriz/efeitos dos fármacos Staphylococcus epidermidis/efeitos dos fármacos [Mh] Termos MeSH secundário: Aderência Bacteriana/efeitos dos fármacos Biofilmes/crescimento & desenvolvimento Carbonil Cianeto m-Clorofenil Hidrazona/análogos & derivados Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Glucose/metabolismo Glucose/farmacologia Nigericina/farmacologia Força Próton-Motriz/fisiologia Staphylococcus epidermidis/crescimento & desenvolvimento Staphylococcus epidermidis/metabolismo Valinomicina/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Ionophores); 2001-95-8 (Valinomycin); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); 946-76-9 (carbonylcyanide 4-chlorophenylhydrazone); IY9XDZ35W2 (Glucose); RRU6GY95IS (Nigericin) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171024 [Lr] Data última revisão: 171024 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170831 [St] Status: MEDLINE

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[PMID]: 27789709 [Au] Autor: Gleyzer N; Scarpulla RC [Ad] Endereço: From the Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611. [Ti] Título: Concerted Action of PGC-1-related Coactivator (PRC) and c-MYC in the Stress Response to Mitochondrial Dysfunction. [So] Source: J Biol Chem;291(49):25529-25541, 2016 Dec 02. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PGC-1-related coactivator (PRC) has a dual function in growth-regulated mitochondrial biogenesis and as a sensor of metabolic stress. PRC induction by mitochondrial inhibitors, intracellular ROS, or topoisomerase I inhibition orchestrates an inflammatory program associated with the adaptation to cellular stress. Activation of this program is accompanied by the coordinate expression of c-MYC, which is linked kinetically to that of PRC in response to multiple stress inducers. Here, we show that the c-MYC inhibitor 10058-F4 blocks the induction of c-MYC, PRC, and representative PRC-dependent stress genes by the respiratory chain uncoupler, carbonyl cyanide m-chlorophenyl hydrazine (CCCP). This result, confirmed by the suppression of PRC induction by c-MYC siRNA silencing, demonstrates a requirement for c-MYC in orchestrating the stress program. PRC steady-state expression was markedly increased upon mutation of two GSK-3 serine phosphorylation sites within the carboxyl-terminal domain. The negative control of PRC expression by GSK-3 was consistent with the phosphor-inactivation of GSK-3ß by CCCP and by the induction of PRC by the GSK-3 inhibitor AZD2858. Unlike PRC, which was induced post-translationally through increased protein half-life, c-MYC was induced predominantly at the mRNA level. Moreover, suppression of Akt activation by the Akt inhibitor MK-2206 blocked the CCCP induction of PRC, c-MYC, and representative PRC stress genes, demonstrating a requirement for Akt signaling. MK-2206 also inhibited the phosphor-inactivation of GSK-3ß by CCCP, a result consistent with the ability of Akt to phosphorylate, and thereby suppress GSK-3 activity. Thus, PRC and c-MYC can act in concert through Akt-GSK-3 signaling to reprogram gene expression in response to mitochondrial stress. [Mh] Termos MeSH primário: Mitocôndrias/metabolismo Proteínas Proto-Oncogênicas c-myc/metabolismo Transdução de Sinais Estresse Fisiológico Fatores de Transcrição/metabolismo [Mh] Termos MeSH secundário: Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Linhagem Celular Tumoral Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores Glicogênio Sintase Quinase 3 beta/genética Glicogênio Sintase Quinase 3 beta/metabolismo Compostos Heterocíclicos com 3 Anéis/farmacologia Seres Humanos Mitocôndrias/genética Fosforilação/efeitos dos fármacos Fosforilação/genética Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores Proteínas Proto-Oncogênicas c-akt/genética Proteínas Proto-Oncogênicas c-akt/metabolismo Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores Pirazinas/farmacologia Sulfonamidas/farmacologia Tiazóis/farmacologia Fatores de Transcrição/antagonistas & inibidores Fatores de Transcrição/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one); 0 (AZD2858); 0 (Heterocyclic Compounds, 3-Ring); 0 (MK 2206); 0 (MYC protein, human); 0 (Proto-Oncogene Proteins c-myc); 0 (Pyrazines); 0 (Sulfonamides); 0 (Thiazoles); 0 (Transcription Factors); 0 (peroxisome-proliferator-activated receptor-gamma coactivator-1); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170526 [Lr] Data última revisão: 170526 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161030 [St] Status: MEDLINE

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[PMID]: 27667687 [Au] Autor: Mills EL; Kelly B; Logan A; Costa ASH; Varma M; Bryant CE; Tourlomousis P; Däbritz JHM; Gottlieb E; Latorre I; Corr SC; McManus G; Ryan D; Jacobs HT; Szibor M; Xavier RJ; Braun T; Frezza C; Murphy MP; O'Neill LA [Ad] Endereço: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. [Ti] Título: Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. [So] Source: Cell;167(2):457-470.e13, 2016 Oct 06. [Is] ISSN: 1097-4172 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state. [Mh] Termos MeSH primário: Inflamação/imunologia Ativação de Macrófagos Macrófagos/imunologia Mitocôndrias/enzimologia Succinato Desidrogenase/metabolismo Ácido Succínico/metabolismo [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Animais Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Ciclo do Ácido Cítrico Glicólise Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo Inflamação/genética Interleucina-10/metabolismo Lipopolissacarídeos/imunologia Macrófagos/metabolismo Malonatos/farmacologia Potencial da Membrana Mitocondrial Camundongos Camundongos Endogâmicos C57BL Mitocôndrias/efeitos dos fármacos Proteínas Mitocondriais/metabolismo Oxirredução/efeitos dos fármacos Fosforilação Oxidativa/efeitos dos fármacos Oxirredutases/metabolismo Proteínas de Plantas/metabolismo Espécies Reativas de Oxigênio/metabolismo Análise de Sequência de RNA Succinato Desidrogenase/genética Transcriptoma [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Hif1a protein, mouse); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (IL10 protein, mouse); 0 (Lipopolysaccharides); 0 (Malonates); 0 (Mitochondrial Proteins); 0 (Plant Proteins); 0 (Reactive Oxygen Species); 130068-27-8 (Interleukin-10); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); 8L70Q75FXE (Adenosine Triphosphate); AB6MNQ6J6L (Succinic Acid); EC 1.- (Oxidoreductases); EC 1.- (alternative oxidase); EC 1.3.99.1 (Succinate Dehydrogenase); EM8Y79998C (methyl malonate) [Em] Mês de entrada: 1701 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160927 [St] Status: MEDLINE

10 / 2087

MEDLINE

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[PMID]: 27634387 [Au] Autor: Park J; Tran Q; Mun K; Masuda K; Kwon SH; Kim SH; Kim DH; Thomas G; Park J [Ad] Endereço: Department of Pharmacology and Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 35015, South Korea; Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH 45437, USA. [Ti] Título: Involvement of S6K1 in mitochondria function and structure in HeLa cells. [So] Source: Cell Signal;28(12):1904-1915, 2016 Dec. [Is] ISSN: 1873-3913 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The major biological function of mitochondria is to generate cellular energy through oxidative phosphorylation. Apart from cellular respiration, mitochondria also play a key role in signaling processes, including aging and cancer metabolism. It has been shown that S6K1-knockout mice are resistant to obesity due to enhanced beta-oxidation, with an increased number of large mitochondria. Therefore, in this report, the possible involvement of S6K1 in regulating mitochondria dynamics and function has been investigated in stable lenti-shS6K1-HeLa cells. Interestingly, S6K1-stably depleted HeLa cells showed phenotypical changes in mitochondria morphology. This observation was further confirmed by detailed image analysis of mitochondria shape. Corresponding molecular changes were also observed in these cells, such as the induction of mitochondrial fission proteins (Drp1 and Fis1). Oxygen consumption is elevated in S6K1-depeleted HeLa cells and FL5.12 cells. In addition, S6K1 depletion leads to enhancement of ATP production in cytoplasm and mitochondria. However, the relative ratio of mitochondrial ATP to cytoplasmic ATP is actually decreased in lenti-shS6K1-HeLa cells compared to control cells. Lastly, induction of mitophagy was found in lenti-shS6K1-HeLa cells with corresponding changes of mitochondria shape on electron microscope analysis. Taken together, our results indicate that S6K1 is involved in the regulation of mitochondria morphology and function in HeLa cells. This study will provide novel insights into S6K1 function in mitochondria-mediated cellular signaling. [Mh] Termos MeSH primário: Mitocôndrias/metabolismo Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo [Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia Células HeLa Seres Humanos Espaço Intracelular/metabolismo Mitocôndrias/efeitos dos fármacos Degradação Mitocondrial/efeitos dos fármacos Dinâmica Mitocondrial/efeitos dos fármacos Consumo de Oxigênio/efeitos dos fármacos RNA Interferente Pequeno/metabolismo Espécies Reativas de Oxigênio/metabolismo Serina-Treonina Quinases TOR/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (RNA, Small Interfering); 0 (Reactive Oxygen Species); 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone); 8L70Q75FXE (Adenosine Triphosphate); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170929 [Lr] Data última revisão: 170929 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160917 [St] Status: MEDLINE

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