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1.
Biochim Biophys Acta Bioenerg ; 1860(9): 724-733, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31356773

RESUMO

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family. In this work, two members of this family, UCP5 (BMCP1, brain mitochondrial carrier protein 1 encoded by SLC25A14) and UCP6 (KMCP1, kidney mitochondrial carrier protein 1 encoded by SLC25A30) have been thoroughly characterized biochemically. They were overexpressed in bacteria, purified and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that UCP5 and UCP6 transport inorganic anions (sulfate, sulfite, thiosulfate and phosphate) and, to a lesser extent, a variety of dicarboxylates (e.g. malonate, malate and citramalate) and, even more so, aspartate and (only UCP5) glutamate and tricarboxylates. Both carriers catalyzed a fast counter-exchange transport and a very low uniport of substrates. Transport was saturable and inhibited by mercurials and other mitochondrial carrier inhibitors at various degrees. The transport affinities of UCP5 and UCP6 were higher for sulfate and thiosulfate than for any other substrate, whereas the specific activity of UCP5 was much higher than that of UCP6. It is proposed that a main physiological role of UCP5 and UCP6 is to catalyze the export of sulfite and thiosulfate (the H2S degradation products) from the mitochondria, thereby modulating the level of the important signal molecule H2S.


Assuntos
Ânions/metabolismo , Ácidos Dicarboxílicos/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfatos/metabolismo , Enxofre/metabolismo , Transporte Biológico , Humanos , Mitocôndrias/metabolismo
2.
Int J Mol Med ; 44(1): 3-15, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115493

RESUMO

The mammalian mitochondrial electron transport chain (ETC) includes complexes I­IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. The first part of this review briefly introduces the structure and function of complexes I­IV and ATP synthase, including the specific electron transfer process in each complex. Some electrons are directly transferred to O2 to generate reactive oxygen species (ROS) in the ETC. The second part of this review discusses the sites of ROS generation in each ETC complex, including sites IF and IQ in complex I, site IIF in complex II and site IIIQo in complex III, and the physiological and pathological regulation of ROS. As signaling molecules, ROS play an important role in cell proliferation, hypoxia adaptation and cell fate determination, but excessive ROS can cause irreversible cell damage and even cell death. The occurrence and development of a number of diseases are closely related to ROS overproduction. Finally, proton leak and uncoupling proteins (UCPS) are discussed. Proton leak consists of basal proton leak and induced proton leak. Induced proton leak is precisely regulated and induced by UCPs. A total of five UCPs (UCP1­5) have been identified in mammalian cells. UCP1 mainly plays a role in the maintenance of body temperature in a cold environment through non­shivering thermogenesis. The core role of UCP2­5 is to reduce oxidative stress under certain conditions, therefore exerting cytoprotective effects. All diseases involving oxidative stress are associated with UCPs.


Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Proteínas de Desacoplamento Mitocondrial/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Termogênese , Animais , Hipóxia Celular , Proliferação de Células , Humanos , Proteínas de Desacoplamento Mitocondrial/genética
3.
PLoS One ; 14(1): e0210592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629714

RESUMO

Plant UCPs are proved to take part in the fine-tuning of mitochondrial ROS generation. It has emerged that mitochondrion can be an important early source of intracellular ROS during plant-pathogen interaction thus plant UCPs must also play key role in this redox fine-tuning during the early phase of plant-pathogen interaction. On the contrary of this well-established assumption, the expression of plant UCPs and their activity has not been investigated in elicitor induced oxidative burst. Thus, the level of plant UCPs both at RNA and protein level and their activity was investigated and compared to AOX as a reference in Arabidopsis thaliana cells due to bacterial harpin treatments. Similar to the expression and activity of AOX, the transcript level of UCP4, UCP5 and the UCP activity increased due to harpin treatment and the consequential oxidative burst. The expression of UCP4 and UCP5 elevated 15-18-fold after 1 h of treatment, then the activity of UCP reached its maximal value at 4h of treatment. The quite rapid activation of UCP due to harpin treatment gives another possibility to fine tune the redox balance of plant cell, furthermore explains the earlier observed rapid decrease of mitochondrial membrane potential and consequent decrease of ATP synthesis after harpin treatment.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/microbiologia , Interações Hospedeiro-Patógeno , Proteínas Mitocondriais/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Oxirredutases/metabolismo , Proteínas de Plantas/metabolismo , Pseudomonas syringae/fisiologia , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas da Membrana Bacteriana Externa/metabolismo , Regulação da Expressão Gênica de Plantas , Potencial da Membrana Mitocondrial , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas de Desacoplamento Mitocondrial/genética , Oxirredução , Oxirredutases/genética , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória
4.
Food Funct ; 10(1): 235-243, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30540319

RESUMO

Housefly (Musca domestica) Larvae powder (HL) is rich in antioxidants. As oxidative stress is considered as one of the main pathogenesis in Alzheimer's Disease (AD), this study was designed to explore the protective effects of HL as an antioxidant on APP/PS1 mice. 2-Month-old APP/PS1 mice were divided into a model control (MC) group, a Donepezil group and a HL group, and C57BL/6 mice were used as the normal control (NC) group. After 180 days of treatment, the memory ability was measured by Morris Water Maze (MWM). The presence of Aß and the expression of Uncoupling Protein 4 (UCP4) and CyclinD1 were detected by immunohistochemistry. The expressions of Superoxide Dismutase 1 (SOD1), Catalase (CAT) and Mitogen-activated Protein Kinase (MAPK) signal pathways were measured by western blotting. Compared with untreated APP/PS1 mice, the memory abilities of the HL-treated mice were significantly improved. Furthermore, the HL treatment not only down-regulated the deposition of Aß and the expression of CylinD1, but also increased both the mRNA and protein levels of SOD, CAT, and UCP4, and enhanced the phosphorylation of JNK and P38 MAPK activation. In conclusion, these results suggest that HL may have a protective effect against memory impairment and prevent oxidative stress-induced injury via the regulation of UCP4 and CyclinD1 and the modulation of JNK and P38 MAPK signaling in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ciclina D1/metabolismo , Moscas Domésticas/química , Proteínas de Desacoplamento Mitocondrial/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Animais , Ciclina D1/genética , Modelos Animais de Doenças , Moscas Domésticas/crescimento & desenvolvimento , Humanos , Larva/química , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Desacoplamento Mitocondrial/genética , Fármacos Neuroprotetores/química , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Neurosci Lett ; 696: 140-145, 2019 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-30582970

RESUMO

Uncoupling proteins (UCPs) belong to the mitochondrial anion carrier superfamily and catalyze important metabolic functions at the mitochondrial inner membrane. While the thermogenic role of UCP1 in brown fat of eutherian mammals is well established, the molecular functions of UCP1 in ectothermic vertebrates and of other UCP paralogs remain less clear. Here, we critically discuss the existence of brain UCPs and their potential roles. Applying phylogenetic classification of novel UCPs, we summarize the evidence for brain UCP1 among vertebrates, the role of UCP2 in specific brain areas, and the existence of brain-specific UCPs. The phylogenetic analyses and discussion on functional data should alert the scientific community that the molecular function of so-called UCP1 homologues is by far not clarified and possibly relates to neither thermogenesis nor mitochondrial uncoupling.


Assuntos
Encéfalo/metabolismo , Canais Iônicos/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Animais , Evolução Molecular , Humanos , Filogenia
6.
Aging (Albany NY) ; 10(11): 3283-3293, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425186

RESUMO

Ongoing research suggests that mitochondrial dysfunction is a common hallmark in neurodegenerative diseases, pointing to mitochondrial uncoupling process as a critical player. We recently reported that rs9472817-C/G, an intronic variant of neuronal mitochondrial uncoupling protein-4 (UCP4/SLC25A27) gene affects the risk of late onset Alzheimer's disease (LOAD), and that the variant's effect is strongly dependent on APOE-ε4 status. Here, we extended our analysis to a cohort of 751 subjects including late-onset familial and sporadic cases of frontotemporal dementia (FTD; 213), Parkinson disease (PD;96), and 442 healthy controls. In all subgroups, carriers of APOE-ε4 allele were at higher risk of disease. Regarding the rs9472817, no association was detected in familial FTD and both subgroups of PD patients. In sporadic FTD, as in LOAD, we found that the C allele increased the risk of disease of about 1.51-fold in a dose-dependent manner (p=0.013) independently from that conferred by APOE-ε4. Expression quantitative trait loci (eQTL) data of different brain regions suggest that rs9472817 likely exerts its effect by a cis-regulatory mechanism involving modulation of UCP4. If validated, the involvement of UCP4 in both FTD and LOAD might indicate interesting shared etiological factors which might give future therapeutic clues.


Assuntos
Demência Frontotemporal/genética , Predisposição Genética para Doença , Proteínas de Desacoplamento Mitocondrial/metabolismo , Doença de Parkinson/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Demência Frontotemporal/metabolismo , Genótipo , Humanos , Masculino , Proteínas de Desacoplamento Mitocondrial/genética , Doença de Parkinson/metabolismo
7.
Handb Clin Neurol ; 157: 623-633, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459028

RESUMO

Phenethylamine-induced hyperthermia can occur following exposure to several different types of illicit stimulants, such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine ("Molly"), synthetic cathinones ("bath salts"), and N-methoxybenyl ("NBOMe"), to name a few. Peripheral norepinephrine release mediated by these sympathomimetic agents induces a double-edged sword of heat accumulation through ß-adrenoreceptor-dependent activation of uncoupling protein (UCP1 and 3)-regulated thermogenesis and loss of heat dissipation through α1-adrenoreceptor-mediated vasoconstriction. Additionally, thyroid hormones are important determinants of the capacity of thermogenesis induced by phenethylamines through the regulation of free fatty acid release and the transcriptional activation of a host of metabolic genes, including adrenergic receptors and mitochondrial uncoupling proteins. Here, we review the central and peripheral mechanistic "triggers" of phenethylamine-induced hyperthermia and outline potential pharmacologic interventions for managing phenethylamine-induced hyperthermia based on these recently discovered hyperthermia mediators.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Febre/induzido quimicamente , Fenetilaminas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/complicações , Animais , Regulação da Temperatura Corporal/fisiologia , Humanos , Proteínas de Desacoplamento Mitocondrial/metabolismo , Norepinefrina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/etiologia
8.
J Exp Biol ; 221(Pt 24)2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30352820

RESUMO

Thermal effects on mitochondrial efficiency and ATP production can influence whole-animal thermal tolerance and performance. Thus, organisms may have the capacity to alter mitochondrial processes through acclimation or adaptation to mitigate these effects. One possible mechanism is through the action of uncoupling proteins (UCPs), which can decrease the proton-motive force independent of the production of ATP. To test this hypothesis, we examined the mRNA expression patterns of UCP isoforms and characterized the effects of thermal acclimation and putative local thermal adaptation on mitochondrial capacity, proton leak and P/O ratios in two subspecies of Atlantic killifish (Fundulus heteroclitus). Ucp1 was the dominant isoform in liver and was more highly expressed in northern killifish. We found that cold acclimation increased mitochondrial capacity (state III and maximum substrate oxidation capacity), state II membrane potential, proton leak and P/O ratios in northern, but not southern, killifish liver mitochondria. Palmitate-induced mitochondrial uncoupling was detected in northern, but not southern, killifish liver mitochondria, consistent with the differences in Ucp mRNA expression between the subspecies. Taken together, our data suggest that mitochondrial function is more plastic in response to thermal acclimation in northern killifish than in southern killifish and that UCP1 may play a role in regulating the proton-motive force in northern, but not southern, killifish in response to thermal acclimation. These data demonstrate the potential for adaptive variation in mitochondrial plasticity in response to cold.


Assuntos
Aclimatação , Proteínas de Peixes/genética , Fundulidae/fisiologia , Expressão Gênica , Temperatura Alta , Mitocôndrias/metabolismo , Proteínas de Desacoplamento Mitocondrial/genética , Animais , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica , Proteínas de Desacoplamento Mitocondrial/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
9.
Arch Biochem Biophys ; 657: 41-55, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217511

RESUMO

The uncoupling protein (UCP1) is a proton (H+) transporter in the mitochondrial inner membrane. By dissipating the electrochemical H+ gradient, UCP1 uncouples respiration from ATP synthesis, which drives an increase in substrate oxidation via the TCA cycle flux that generates more heat. The mitochondrial uncoupling-mediated non-shivering thermogenesis in brown adipose tissue is vital primarily to mammals, such as rodents and new-born humans, but more recently additional functions in adult humans have been described. UCP1 is regulated by ß-adrenergic receptors through the sympathetic nervous system and at the molecular activity level by nucleotides and fatty acid to meet thermogenesis needs. The discovery of novel UCP homologs has greatly contributed to the understanding of human diseases, such as obesity and diabetes. In this article, we review the progress made towards the molecular mechanism and function of the UCPs, in particular focusing on the influential contributions from Martin Klingenberg's laboratory. Because all members of the UCP family are potentially promising drug targets, we also present and discuss possible approaches and methods for UCP-related drug discovery.


Assuntos
Proteínas de Desacoplamento Mitocondrial/química , Proteínas de Desacoplamento Mitocondrial/metabolismo , Trifosfato de Adenosina/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Sítios de Ligação , Ácidos Graxos não Esterificados/metabolismo , Humanos , Ligação Proteica , Termogênese/fisiologia
10.
Prion ; 12(3-4): 216-225, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30009661

RESUMO

Targeted expression of genes coding for proteins specific to astrocytes, oligodendrocytes and myelin was performed in frontal cortex area 8 of Creutzfeldt-Jakob disease methionine/methionine and valine/valine (CJD MM1 and VV2, respectively) compared with controls. GFAP (glial fibrillary acidic protein) mRNA was up-regulated whereas SLC1A2 (solute carrier family 1 member 2, coding for glutamate transporter 1: GLT1), AQ4 (aquaporin 4), MPC1 (mitochondrial pyruvate carrier 1) and UCP5 (mitochondrial uncoupled protein 5) mRNAs were significantly down-regulated in CJD MM1 and CJD VV2, and GJA1 (connexin 43) in CJD VV2. OLIG1 and OLIG2 (oligodendocyte transcription factor 1 and 2, respectively), SOX10 (SRY-Box10) and oligodendroglial precursor cell (OPC) marker NG2 (neuronal/glial antigen) 2 were preserved, but GALC (coding for galactosylceramidase), SLC2A1 (solute carrier family 2 member 1: glucose transporter member 1: GLUT1) and MCT1 (monocarboxylic acid transporter 1) mRNA expression levels were significantly reduced in CJD MM1 and CJD VV2. Expression levels of most genes linked to myelin were not altered in the cerebral cortex in CJD. Immunohistochemistry to selected proteins disclosed individual variations but GFAP, Olig-2, AQ4 and GLUT1 correlated with mRNA levels, whereas GLT1 was subjected to individual variations. However, MPC1, UCP5 and MCT1 decrease was more closely related to the respective reduced neuronal immunostaining. These observations support the idea that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, are relevant in the pathogenesis of cortical lesions in CJD.


Assuntos
Astrócitos/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Lobo Frontal/citologia , Oligodendroglia/metabolismo , Transcrição Genética/genética , Astrócitos/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Lobo Frontal/patologia , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Humanos , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Desacoplamento Mitocondrial/genética , Proteínas de Desacoplamento Mitocondrial/metabolismo , Transportadores de Ácidos Monocarboxílicos , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/patologia , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
J Biol Chem ; 293(11): 4213-4227, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29371401

RESUMO

The Arabidopsis thaliana genome contains 58 members of the solute carrier family SLC25, also called the mitochondrial carrier family, many of which have been shown to transport specific metabolites, nucleotides, and cofactors across the mitochondrial membrane. Here, two Arabidopsis members of this family, AtUCP1 and AtUCP2, which were previously thought to be uncoupling proteins and hence named UCP1/PUMP1 and UCP2/PUMP2, respectively, are assigned with a novel function. They were expressed in bacteria, purified, and reconstituted in phospholipid vesicles. Their transport properties demonstrate that they transport amino acids (aspartate, glutamate, cysteine sulfinate, and cysteate), dicarboxylates (malate, oxaloacetate, and 2-oxoglutarate), phosphate, sulfate, and thiosulfate. Transport was saturable and inhibited by mercurials and other mitochondrial carrier inhibitors to various degrees. AtUCP1 and AtUCP2 catalyzed a fast counterexchange transport as well as a low uniport of substrates, with transport rates of AtUCP1 being much higher than those of AtUCP2 in both cases. The aspartate/glutamate heteroexchange mediated by AtUCP1 and AtUCP2 is electroneutral, in contrast to that mediated by the mammalian mitochondrial aspartate glutamate carrier. Furthermore, both carriers were found to be targeted to mitochondria. Metabolite profiling of single and double knockouts shows changes in organic acid and amino acid levels. Notably, AtUCP1 and AtUCP2 are the first reported mitochondrial carriers in Arabidopsis to transport aspartate and glutamate. It is proposed that the primary function of AtUCP1 and AtUCP2 is to catalyze an aspartateout/glutamatein exchange across the mitochondrial membrane and thereby contribute to the export of reducing equivalents from the mitochondria in photorespiration.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Ácido Aspártico/metabolismo , Ácidos Dicarboxílicos/metabolismo , Ácido Glutâmico/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Proteína Desacopladora 1/metabolismo , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Metaboloma , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas de Desacoplamento Mitocondrial/genética , Proteína Desacopladora 1/genética
12.
Antioxid Redox Signal ; 29(7): 667-714, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351723

RESUMO

SIGNIFICANCE: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.


Assuntos
Antioxidantes/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Transdução de Sinais , Animais , Humanos , Oxirredução
13.
J Sci Food Agric ; 98(10): 3715-3721, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29315586

RESUMO

BACKGROUND: Heat stress (HS) is detrimental to animal-origin food production. Artemisia annua L., a natural source of phenolic compounds and flavonoids, exhibits antioxidant properties. This study was conducted to evaluate the effects of dietary enzymatically treated Artemisia annua L. (EA) supplementation on meat quality, antioxidant capacity, and energy status of breast muscle in heat-stressed broilers. RESULTS: The inclusion of EA increased the redness, reduced drip loss, decreased reactive oxygen metabolites and thiobarbituric acid-reactive substances, increased antioxidant enzyme activities, and reduced the ferric reducing antioxidant power and free-radical scavenging abilities of breast muscle in heat-treated broilers. Dietary EA supplementation increased adenosine phosphate concentrations and energy charge, and decreased the mRNA expression levels of heat-shock protein 70 and 90, but increased the mRNA expression levels of avian uncoupling protein, peroxisome proliferator-activated receptor-γ coactivator-1α, and sirtuin 1 in the breast muscle of broilers exposed to HS. CONCLUSION: Dietary EA supplementation improved meat quality, antioxidant capacity, and energy status in breast muscle of heat-stressed broilers, which might be associated with altering pertinent mRNA expression; EA could therefore be used as a promising feed additive to mitigate HS in the poultry industry. This study recommended 1.00-1.25 g/kg EA in broiler diet. © 2018 Society of Chemical Industry.


Assuntos
Antioxidantes/análise , Artemisia annua/metabolismo , Galinhas/metabolismo , Suplementos Nutricionais/análise , Músculo Esquelético/química , Ração Animal/análise , Animais , Antioxidantes/metabolismo , Artemisia annua/química , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Galinhas/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Temperatura Alta , Proteínas de Desacoplamento Mitocondrial/genética , Proteínas de Desacoplamento Mitocondrial/metabolismo , Músculo Esquelético/metabolismo , Controle de Qualidade , Estresse Fisiológico
15.
Mol Cells ; 40(11): 864-870, 2017 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-29081084

RESUMO

The uncoupling protein 4 (ucp-4) gene is involved in age-dependent neurodegeneration in C. elegans. Therefore, we aimed to investigate the mechanism underlying the association between mitochondrial uncoupling and neurodegeneration by examining the effects of uncoupling agents and ucp-4 overexpression in C. elegans. Treatment with either DNP or CCCP improved neuronal defects in wild type during aging. Uncoupling agents also restored neuronal phenotypes of ucp-4 mutants to those exhibited by wild type, while ucp-4 overexpression attenuated the severity of age-dependent neurodegeneration. Neuronal improvements were further associated with reductions in mitochondrial membrane potentials. However, these age-dependent neuroprotective effects were limited in mitophagy-deficient mutant, pink-1, background. These results suggest that membrane uncoupling can attenuate age-dependent neurodegeneration by stimulating mitophagy.


Assuntos
2,4-Dinitrofenol/farmacologia , Envelhecimento/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Desacoplamento Mitocondrial/genética , Doenças Neurodegenerativas/etiologia , Organofosfonatos/farmacologia , Piperazinas/farmacologia , 2,4-Dinitrofenol/uso terapêutico , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Proteínas de Desacoplamento Mitocondrial/metabolismo , Mutação , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Organofosfonatos/uso terapêutico , Piperazinas/uso terapêutico
16.
Methods Mol Biol ; 1670: 143-165, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28871541

RESUMO

We describe detailed procedures to get intact and well-coupled mitochondria from a variety of fruit species such as papaya (Carica papaya), guava (Psidium guajava), tomato (Solanum lycopersicum), and strawberry (Fragaria x ananassa) as well as the protocols to assess the capacities of AOX and UCP pathways in intact fruit mitochondria. The procedures presented here were tested for the species mentioned above; their use with other types of fruits must be tested for yield of intact and active mitochondria. This is possible from individual adjustments. Strict care during extraction, including the use of osmotic protectants (i.e., mannitol/sucrose) and antioxidants (i.e., cysteine, ascorbate) at defined concentrations, are critical factors to ensure mitochondrial integrity and to obtain higher yields. The mitochondria purified using the discontinuous Percoll gradients described here can be used for the analysis of the capacity of alternative respiration and uncoupling pathways in fruits. In addition, protocols for quantitative and semiquantitative PCR applicable for the analysis of AOX and UCP gene expression in fruits are shown. Microarray and RNA-seq data from public databases are also valuable for the analysis of AOX and UCP genes. In both cases having the sequences of genes or cDNAs to be used in primer design or probe identification is necessary.


Assuntos
Fracionamento Celular/métodos , Frutas/genética , Regulação da Expressão Gênica de Plantas , Mitocôndrias/metabolismo , Respiração Celular/genética , Genes de Plantas , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Anotação de Sequência Molecular , Oxirredutases/metabolismo , Consumo de Oxigênio , Proteínas de Plantas/metabolismo
17.
Genet Test Mol Biomarkers ; 21(9): 531-538, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28704105

RESUMO

BACKGROUND: Obesity, one of the most common disorders observed in clinical practice, has been associated with energy metabolism-related protein genes such as uncoupling proteins (UCPs). Herein, we evaluated UCPs as candidate genes for obesity and its morbidities. METHODS: A total of 268 obese and 185 nonobese children and adolescents were enrolled in this study. To determine dyslipidemia, hypertension, and insulin resistance, laboratory tests were derived from fasting blood samples. UCP1-3826 A/G, UCP2 exon 8 deletion/insertion (del/ins), and UCP3-55C/T variants were also genotyped, and the relationships among the polymorphisms of these UCPs and obesity morbidities were investigated. RESULTS: The mean ages of the obese and control groups were 11.61 ± 2.83 and 10.74 ± 3.36 years, respectively. The respective genotypic frequencies of the AA, AG, and GG genotypes of UCP1 were 46.3%, 33.2%, and 20.5% in obese subjects and 46.5%, 42.2%, and 11.4% in the controls (p = 0.020). G alleles were more frequent in obese subjects with hypertriglyceridemia (42.9%; p = 0.048) than in those without, and the GG genotype presented an odds ratio for obesity of 2.02 (1.17-3.47; p = 0.010). The polymorphisms of UCP2 exon 8 del/ins and UCP3-55C/T did not influence obesity risk (p > 0.05). The I (ins) allele was associated with low HDL cholesterolemia (p = 0.023). CONCLUSION: The GG genotype of the UCP1-3826 A/G polymorphism appears to contribute to the onset of childhood obesity in Turkish children. The GG genotype of UCP1, together with the del/del genotype of the UCP2 polymorphism, may increase the risk of obesity with synergistic effects. The ins allele of the UCP2 exon 8 del/ins polymorphism may contribute to low HDL cholesterolemia.


Assuntos
Proteínas de Desacoplamento Mitocondrial/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 2/genética , Adolescente , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Criança , Metabolismo Energético , Éxons , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Humanos , Canais Iônicos/genética , Masculino , Proteínas Mitocondriais/genética , Proteínas de Desacoplamento Mitocondrial/metabolismo , Obesidade/genética , Obesidade Pediátrica/genética , Obesidade Pediátrica/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Turquia , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 2/metabolismo , Proteína Desacopladora 3/genética , Proteína Desacopladora 3/metabolismo
18.
Free Radic Biol Med ; 110: 381-389, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28690197

RESUMO

This study investigated the effects of high-fat (HF) diet on parameters of oxidative stress among muscles with distinct fiber type composition and oxidative capacities. To accomplish that, male Wistar rats were fed either a low-fat standard chow (SC) or a HF diet for 8 weeks. Soleus, extensor digitorum longus (EDL), and epitrochlearis muscles were collected and mitochondrial H2O2 (mtH2O2) emission, palmitate oxidation, and gene expression and antioxidant system were measured. Chronic HF feeding enhanced fat oxidation in oxidative and glycolytic muscles. It also caused a significant reduction in mtH2O2 emission in the EDL muscle, although a tendency towards a reduction was also found in the soleus and epitrochlearis muscles. In the epitrochlearis, HF diet increased mRNA expression of the NADPH oxidase complex; however, this muscle also showed an increase in the expression of antioxidant proteins, suggesting a higher capacity to generate and buffer ROS. The soleus muscle, despite being highly oxidative, elicited H2O2 emission rates equivalent to only 20% and 35% of the values obtained for EDL and epitrochlearis muscles, respectively. Furthermore, the Epi muscle with the lowest oxidative capacity was the second highest in H2O2 emission. In conclusion, it appears that intrinsic differences related to the distribution of type I and type II fibers, rather than oxidative capacity, drove the activity of the anti- and pro-oxidant systems and determine ROS production in different skeletal muscles. This also suggests that the impact of potentially deleterious effects of ROS production on skeletal muscle metabolism/function under lipotoxic conditions is fiber type-specific.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , NADPH Oxidases/genética , Obesidade/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Mitocôndrias/patologia , Proteínas de Desacoplamento Mitocondrial/genética , Proteínas de Desacoplamento Mitocondrial/metabolismo , Contração Muscular/fisiologia , Fibras Musculares Esqueléticas/classificação , Fibras Musculares Esqueléticas/patologia , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , NADPH Oxidases/metabolismo , Obesidade/etiologia , Obesidade/patologia , Especificidade de Órgãos , Oxirredução , Estresse Oxidativo , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Ratos , Ratos Wistar
19.
J Lipid Res ; 58(7): 1362-1373, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28473603

RESUMO

Hepatic mitochondrial function, APOC-III, and LPL are potential targets for triglyceride (TG)-lowering drugs. After 3 weeks of dietary treatment with the compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), the hepatic mitochondrial FA oxidation increased more than 5-fold in male Wistar rats. Gene expression analysis in liver showed significant downregulation of APOC-III and upregulation of LPL and the VLDL receptor. This led to lower hepatic (53%) and plasma (73%) TG levels. Concomitantly, liver-specific biomarkers related to mitochondrial biogenesis and function (mitochondrial DNA, citrate synthase activity, and cytochrome c and TFAM gene expression) were elevated. Interestingly, 1-triple TTA lowered plasma acetylcarnitine levels, whereas the concentration of ß-hydroxybutyrate was increased. The hepatic energy state was reduced in 1-triple TTA-treated rats, as reflected by increased AMP/ATP and decreased ATP/ADP ratios, whereas the energy state remained unchanged in muscle and heart. The 1-triple TTA administration induced gene expression of uncoupling protein (UCP)2 and UCP3 in liver. In conclusion, the 1-triple TTA-mediated clearance of blood TG may result from lowered APOC-III production, increased hepatic LPL gene expression, mitochondrial FA oxidation, and (re)uptake of VLDL facilitating drainage of FAs to the liver for ß-oxidation and production of ketone bodies as extrahepatic fuel. The possibility that UCP2 and UCP3 mediate a moderate degree of mitochondrial uncoupling should be considered.


Assuntos
Apolipoproteína C-III/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Triglicerídeos/sangue , Ácido Acético/química , Ácido Acético/farmacologia , Acetilcarnitina/metabolismo , Animais , Carnitina/metabolismo , Metabolismo Energético/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Oxirredução , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
20.
Curr Mol Med ; 17(9): 598-607, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29521228

RESUMO

In metabolic diseases such as obesity, metabolic syndrome and type II diabetes, the over-expression of uncoupling proteins (UCPs) in a response to increased reactive oxygen species (ROS) generation by mitochondrial respiratory complexes, and to the excess of free fatty acid (FFA) supply from adipose tissue, may protect cells from oxidative stress, lipotoxicity and in turn from death. UCPs by reducing superoxide anion and H2O2 generation trigger several signals to cell for their adaptation to the lipotoxic microenvironment. In mitochondria, a decrease of cytochrome c (cyt c) and proapoptotic protein release promotes cell survival and proliferation. The altered lipid metabolism also affects cardiolipin susceptibility to the peroxidation, a process involved in the dissociation of cyt c from mitochondrial inner membrane and its release, a key step of apoptosis. Therefore, UCPs by attenuating ROS generation and lipotoxicity may downregulate programmed cell death, a well-known physiological process controlling cell proliferation contributing to uncontrolled cell proliferation and tumorigenesis. In addition, tumor cells over-expressed UCPs, by inhibiting ROS generation acquire resistance to death during pharmacological treatment with oxidative stress drug inducers. Therefore, the aim of this review is to discuss recent findings regarding the role that UCPs play in cell survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote cell proliferation.


Assuntos
Carcinogênese/patologia , Proliferação de Células , Doenças Metabólicas/fisiopatologia , Proteínas de Desacoplamento Mitocondrial/metabolismo , Neoplasias/fisiopatologia , Animais , Carcinogênese/metabolismo , Humanos
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