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PGC-1α: a metabolic regulator
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De modo a garantir a sobrevivência, os organismos vivos estão numa batalha
constante para manter a homeostase energética, um processo fisiológico robusto e
coordenado que pode ser definido como a regulação do equilíbrio entre a produção e o gasto
de energia. Este processo requer a capacidade de os organismos adaptarem-se a mudanças
ambientais, como no caso de atividades físicas extenuantes ou durante um estado de jejum.
De maneira a atender às necessidades de ATP, as nossas células usam diferentes
modalidades do metabolismo energético na presença ou ausência de oxigênio para produção
de energia. Descoberto inicialmente como uma proteína que regulava a termogénese
adaptativa na presença de frio por meio da interação com PPAR-γ, o PGC-1α foi considerado
um fator central no metabolismo energético. Logo após foram também identificados dois
homólogos, o PGC-1β e PRC, e várias isoformas. O PGC-1α funciona como o agente principal
da biogénese mitocondrial e fosforilação oxidativa, no entanto, novos dados ao longo dos anos
mostraram que o papel fisiológico do PGC-1α estende-se para além do controlo restrito do
metabolismo energético, sendo um participante chave na angiogénese, músculo esquelético,
gliconeogénese, função cardíaca e outros numerosos processos. A disfunção metabólica é
uma característica comum observada em muitas doenças, estas geralmente acompanhadas
por uma desregulação na atividade do PGC-1α. Devido a este papel fundamental na
homeostase energética, revela-se assim um potencial alvo terapêutico bastante atraente em
diversas doenças metabólicas e degenerativas que frequentemente acompanham o avançar
da idade. Consequentemente, regular a ação de PGC-1α aumentando sua atividade em certos
tecidos apresenta uma terapia adequada e interessante numa grande variedade de
patologias, como a sarcopenia, doenças cardiovasculares, doenças neurodegenerativas,
síndrome metabólico, diabetes tipo 2 e até mesmo no cancro. O objetivo desta revisão é
elucidar como é que o PGC-1α e suas isoformas desempenham suas atividades fisiológicas
no organismo, mostrar dados atuais sobre como o PGC-1α está implicado na saúde e na
doença, lacunas na literatura e alguns obstáculos que poderemos enfrentar no futuro no que
diz respeito ao seu uso terapêutico.
To assure survivability, living organisms are in a constant battle to maintain energy homeostasis, a robust and coordinated physiological process that can be defined as the regulation of the balance between energy production and expenditure. This process requires the capacity for organisms to adapt in environmental changes like in strenuous physical activity or a fasted state, to fulfill the organism’s ATP needs, our cells will enroll in different modalities of energy metabolism in the presence or absence of oxygen. Initially discovered as a protein that regulated adaptive thermogenesis in the presence of cold through interaction with PPARγ, PGC-1α was considered a central factor in energy metabolism. Soon after two homologues, PGC-1β and PRC, were identified same with several PGC-1α isoforms. PGC-1α acts as a main driver of mitochondrial biogenesis and oxidative phosphorylation, nonetheless, new data throughout the years have showed us that PGC-1α physiological role extends beyond the strict control of energy metabolism but it is also a key participant in angiogenesis, skeletal muscle fiber-type switching, gluconeogenesis, normal heart function, and other numerous processes. Metabolic dysfunction is a common feature seen in plenty of diseases that generally are accompanied by PGC-1α impairment and dysregulation. Due to this family key role in energy homeostasis, it is unveiled a quite attractive therapeutic potential in various metabolic and degenerative diseases that commonly accompany old age. Hence regulating PGC-1α action by increasing its activity in certain tissues presents a suitable and interesting therapy in a plethora of conditions such as skeletal muscle waste and sarcopenia, cardiovascular disease, neurodegenerative conditions, metabolic syndrome, type 2 diabetes and even cancer. The goal of this review is to shed some light on how PGC-1α and its isoforms perform their physiological activities in the whole body, show novel insights of the current literature about how PGC-1α is implicated in health and disease, knowledge gaps, and some obstacles we might face in the future in regards of its therapeutic use.
To assure survivability, living organisms are in a constant battle to maintain energy homeostasis, a robust and coordinated physiological process that can be defined as the regulation of the balance between energy production and expenditure. This process requires the capacity for organisms to adapt in environmental changes like in strenuous physical activity or a fasted state, to fulfill the organism’s ATP needs, our cells will enroll in different modalities of energy metabolism in the presence or absence of oxygen. Initially discovered as a protein that regulated adaptive thermogenesis in the presence of cold through interaction with PPARγ, PGC-1α was considered a central factor in energy metabolism. Soon after two homologues, PGC-1β and PRC, were identified same with several PGC-1α isoforms. PGC-1α acts as a main driver of mitochondrial biogenesis and oxidative phosphorylation, nonetheless, new data throughout the years have showed us that PGC-1α physiological role extends beyond the strict control of energy metabolism but it is also a key participant in angiogenesis, skeletal muscle fiber-type switching, gluconeogenesis, normal heart function, and other numerous processes. Metabolic dysfunction is a common feature seen in plenty of diseases that generally are accompanied by PGC-1α impairment and dysregulation. Due to this family key role in energy homeostasis, it is unveiled a quite attractive therapeutic potential in various metabolic and degenerative diseases that commonly accompany old age. Hence regulating PGC-1α action by increasing its activity in certain tissues presents a suitable and interesting therapy in a plethora of conditions such as skeletal muscle waste and sarcopenia, cardiovascular disease, neurodegenerative conditions, metabolic syndrome, type 2 diabetes and even cancer. The goal of this review is to shed some light on how PGC-1α and its isoforms perform their physiological activities in the whole body, show novel insights of the current literature about how PGC-1α is implicated in health and disease, knowledge gaps, and some obstacles we might face in the future in regards of its therapeutic use.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
PGC-1α Homeostasia energética Biogénese mitocondrial Metabolismo oxidativo Doença metabólica Mestrado integrado - 2021