Assuntos
Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Indígenas Sul-Americanos , Povos Indígenas , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Adulto , Brasil/epidemiologia , COVID-19 , Pré-Escolar , Infecções por Coronavirus/prevenção & controle , Atenção à Saúde , Serviço Hospitalar de Emergência , Medo , Feminino , Humanos , Masculino , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controleAssuntos
Secas/estatística & dados numéricos , Agricultura Florestal/estatística & dados numéricos , Aquecimento Global/estatística & dados numéricos , Floresta Úmida , Desenvolvimento Sustentável , Árvores/crescimento & desenvolvimento , Brasil , Desenvolvimento Sustentável/tendências , Incêndios Florestais/estatística & dados numéricosRESUMO
Genomic instability drives tumorigenesis and DNA repair defects are associated with elevated cancer. Metabolic alterations are also observed during tumorigenesis, although a causal relationship between these has not been clearly established. Xeroderma pigmentosum (XP) is a DNA repair disease characterized by early cancer. Cells with reduced expression of the XPC protein display a metabolic shift from OXPHOS to glycolysis, which was linked to accumulation of nuclear DNA damage and oxidants generation via NOX-1. Using XP-C cells, we show that mitochondrial respiratory complex I (CI) is impaired in the absence of XPC, while complex II (CII) is upregulated in XP-C cells. The CI/CII metabolic shift was dependent on XPC, as XPC complementation reverted the phenotype. We demonstrate that mitochondria are the primary source of H2O2 and glutathione peroxidase activity is compromised. Moreover, mtDNA is irreversibly damaged and accumulates deletions. XP-C cells were more sensitive to the mitochondrial inhibitor antimycin A, an effect also prevented in XPC-corrected cells. Our results show that XPC deficiency leads to alterations in mitochondrial redox balance with a CI/CII shift as a possible adaptation to lower CI activity, but at the cost of sensitizing XP-C cells to mitochondrial oxidative stress.
Assuntos
Proteínas de Ligação a DNA/genética , Complexo II de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias/genética , Xeroderma Pigmentoso/genética , Linhagem Celular , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Glutationa Peroxidase/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Deleção de Sequência , Xeroderma Pigmentoso/metabolismoRESUMO
Caloric restriction (CR) protects against many cerebral pathological conditions that are associated with excitotoxic damage and calcium overload, although the mechanisms are still poorly understood. Here we show that CR strongly protects against excitotoxic insults in vitro and in vivo in a manner associated with significant changes in mitochondrial function. CR increases electron transport chain activity, enhances antioxidant defenses, and favors mitochondrial calcium retention capacity in the brain. These changes are accompanied by a decrease in cyclophilin D activity and acetylation and an increase in Sirt3 expression. This suggests that Sirt3-mediated deacetylation and inhibition of cyclophilin D in CR promote the inhibition of mitochondrial permeability transition, resulting in enhanced mitochondrial calcium retention. Altogether, our results indicate that enhanced mitochondrial calcium retention capacity underlies the beneficial effects of CR against excitotoxic conditions. This protection may explain the many beneficial effects of CR in the aging brain.
Assuntos
Cálcio/metabolismo , Restrição Calórica , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/metabolismo , Neurotoxinas/toxicidade , Acetilação/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Peptidil-Prolil Isomerase F , Ciclofilinas/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Ácido Glutâmico/toxicidade , Masculino , Camundongos , Ratos Sprague-Dawley , Soro/metabolismoRESUMO
Aging is often accompanied by a decline in mitochondrial mass and function in different tissues. Additionally, cell resistance to stress is frequently found to be prevented by higher mitochondrial respiratory capacity. These correlations strongly suggest mitochondria are key players in aging and senescence, acting by regulating energy homeostasis, redox balance and signalling pathways central in these processes. However, mitochondria display a wide array of functions and signalling properties, and the roles of these different characteristics are still widely unexplored. Furthermore, differences in mitochondrial properties and responses between tissues and cell types, and how these affect whole body metabolism are also still poorly understood. This review uncovers aspects of mitochondrial biology that have an impact upon aging in model organisms and selected mammalian cells and tissues.
Assuntos
Envelhecimento/fisiologia , Mitocôndrias/metabolismo , Células-Tronco Adultas/metabolismo , Animais , Encéfalo/metabolismo , Caenorhabditis elegans/metabolismo , Metabolismo Energético/fisiologia , Humanos , Modelos Biológicos , Leveduras/metabolismoRESUMO
The maximal capacity of the mitochondrial electron transport system (ETS) in intact cells is frequently estimated by promoting protonophore-induced maximal oxygen consumption preceded by inhibition of oxidative phosphorylation by oligomycin. In the present study, human glioma (T98G and U-87MG) and prostate cancer (PC-3) cells were titrated with different concentrations of the protonophore CCCP to induce maximal oxygen consumption rate (OCR) within respirometers in a conventional growth medium. The results demonstrate that the presence of oligomycin or its A-isomer leads to underestimation of maximal ETS capacity. In the presence of oligomycin, the spare respiratory capacity (SRC), i.e., the difference between the maximal and basal cellular OCR, was underestimated by 25 to 45%. The inhibitory effect of oligomycin on SRC was more pronounced in T98G cells and was observed in both suspended and attached cells. Underestimation of SRC also occurred when oxidative phosphorylation was fully inhibited by the ATP synthase inhibitor citreoviridin. Further experiments indicated that oligomycin cannot be replaced by the adenine nucleotide translocase inhibitors bongkrekic acid or carboxyatractyloside because, although these compounds have effects in permeabilized cells, they do not inhibit oxidative phosphorylation in intact cells. We replaced CCCP by FCCP, another potent protonophore and similar results were observed. Lower maximal OCR and SRC values were obtained with the weaker protonophore 2,4-dinitrophenol, and these parameters were not affected by the presence of oligomycin. In permeabilized cells or isolated brain mitochondria incubated with respiratory substrates, only a minor inhibitory effect of oligomycin on CCCP-induced maximal OCR was observed. We conclude that unless a previously validated protocol is employed, maximal ETS capacity in intact cells should be estimated without oligomycin. The inhibitory effect of an ATP synthase blocker on potent protonophore-induced maximal OCR may be associated with impaired metabolism of mitochondrial respiratory substrates.
Assuntos
Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oligomicinas/farmacologia , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Transporte de Elétrons/efeitos dos fármacos , Humanos , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacosRESUMO
The brain has a central role in the regulation of energy stability of the organism. It is the organ with the highest energetic demands, the most susceptible to energy deficits, and is responsible for coordinating behavioral and physiological responses related to food foraging and intake. Dietary interventions have been shown to be a very effective means to extend lifespan and delay the appearance of age-related pathological conditions, notably those associated with brain functional decline. The present review focuses on the effects of these interventions on brain metabolism and cerebral redox state, and summarizes the current literature dealing with dietary interventions on brain pathology.