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Doctoral Thesis
DOI
10.11606/T.17.2018.tde-26042018-135946
Document
Author
Full name
Tanes Imamura de Lima
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2018
Supervisor
Committee
Silveira, Leonardo dos Reis (President)
Gomes, Marcelo Damario
Mori, Marcelo Alves da Silva
Alberici, Luciane Carla
Pereira, Tiago Campos
Title in Portuguese
Controle molecular da função mitocondrial pelos co-reguladores transcricionais PGC-1? e NCoR1 em células musculares
Keywords in Portuguese
Coreguladores; PGC-1; NCoR1; Mitocôndria; Células musculares
Abstract in Portuguese
A capacidade de sincronizar vias metabólicas a estímulos ambientais é um aspecto central da homeostase em mamíferos. Dentro desse contexto, o controle molecular da função mitocondrial representa um aspecto fundamental e defeitos na integridade desse sistema podem levar a severas perturbações à homeostase celular levando a um amplo espectro de doenças como a obesidade e o diabetes tipo 2. O controle transcricional do metabolismo energético é um processo dinâmico que depende da ação coordenada de fatores de transcrição, enzimas modificadoras de cromatina e coreguladores transcricionais. Co-reguladores podem agir como interruptores transcricionais ativando ou reprimindo a atividade de receptores nucleares. Neste estudo, demonstramos que o coativador PGC-1? e o co-repressor NCoR1 são importantes mediadores do metabolismo energético e da homeostase redox mitocondrial em células musculares. Nossos resultados sugerem que os efeitos desses co-reguladores são mediados pela transativação do elemento responsivo de PPAR (PPRE) em promotores de seletos grupos de genes. Ainda, a indução da capacidade oxidativa e da defesa antioxidante pelo silenciamento de NCoR1 ou pela expressão de PGC-1? atenua a produção de espécies reativas de oxigênio e a morte celular induzida por estresse metabólico. Essas evidências sugerem que o equilíbrio entre a ativação e a repressão transcricional em promotores contendo PPREs exerce um papel central na função mitocondrial em células musculares esqueléticas. Coletivamente, os resultados deste estudo indicam que o antagonismo entre os coreguladores PGC-1? e NCoR1 é um componente central no controle da função mitocondrial representando uma interface promissora para o desenvolvimento de novas abordagens terapêuticas para o tratamento e prevenção da disfunção metabólica.
Title in English
Molecular control of mitochondrial function by the transcriptional co-regulators PGC-1? and NCoR1 in skeletal muscle cells
Keywords in English
Coregulators; Mitochondria; Muscle cells; NCoR1; PGC-1
Abstract in English
The ability to synchronize metabolic pathways to environmental stimuli is a central aspect of mammalian homeostasis. Within this context, the molecular control of mitochondrial function represents a fundamental aspect and defects in the integrity of this system can lead to severe disturbances to cellular homeostasis causing a wide spectrum of pathologies such as obesity and type 2 diabetes. Transcriptional control of energy metabolism is a dynamic process that depends on the coordinated action of transcription factors, chromatin modifying enzymes, and transcriptional co-regulators. Co-regulators can act as transcriptional switches activating or repressing the activity of nuclear receptors. In this study, we demonstrated that the co-activator PGC-1? and NCoR1 co-repressor are essential mediators of energy metabolism and mitochondrial redox homeostasis in muscle cells. Our results suggest that the effects of these co-regulators are mediated by the transactivation of the PPAR responsive elements (PPREs) in promoters of selected gene groups. Furthermore, the oxidative capacity and antioxidant defense induction by either NCoR1 knockdown or PGC-1? overexpression attenuates the production of reactive oxygen species and cell death induced by metabolic stress. These evidence suggest that the balance between activation and transcriptional repression in promoters containing PPREs exert a central role in mitochondrial function in skeletal muscle cells. Collectively, the results of this study indicate that the antagonism between the co-regulators PGC-1? and NCoR1 is a central component of mitochondrial function representing a promising interface for the development of novel therapeutic approaches for the treatment and prevention of metabolic dysfunction.
 
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Publishing Date
2018-05-28
 
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