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BiogĂ©nese mitocondrial como alvo terapĂȘutico e potenciais agentes moduladores
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A mitocĂŽndria Ă© um organelo celular multifuncional, determinante para a sobrevivĂȘncia, diferenciação e morte celular. A necessidade de desenvolvimento de moduladores de certas funçÔes das mitocĂŽndrias Ă© reforçada pela disrupção na homeostasia mitocondrial, evidenciada por uma lista extensa de patologias. A disfunção mitocondrial estĂĄ presente em doenças mitocondriais raras, como consequĂȘncia primĂĄria de mutaçÔes hereditĂĄrias, e em doenças comuns adquiridas num contexto multifatorial associado ao envelhecimento, nomeadamente doenças neurodegenerativas, doenças metabĂłlicas, cardiovasculares e neoplĂĄsicas. Fazem parte deste conjunto complexo de alteraçÔes celulares, os eventos de heteroplasmia, alteraçÔes na proteostase, stress oxidativo, alteraçÔes no fluxo de nutrientes e iĂ”es como o cĂĄlcio, acumulação de mitocĂŽndrias fragmentadas, alteraçÔes no perfil de fatores de transcrição da biogĂ©nese mitocondrial e diminuição da capacidade de fosforilação oxidativa. Neste Ăąmbito, a modulação de fatores que regulam a biogĂ©nese mitocondrial tem como objetivo incrementar a função do organelo atravĂ©s da promoção da expressĂŁo de componentes mitocondriais e, portanto, um melhor desempenho e adaptação bioenergĂ©tica, promovendo, deste modo, mecanismos de proteção e reparação celular. A biogĂ©nese mitocondrial Ă© um processo regulado por uma rede de cascatas de sinalização que convergem na ativação do co-ativador PGC-1α, o principal regulador do processo, e que resultam na ativação de efetores de transcrição mitocondrial NRF1, NRF2 e TFAM, e subsequente expressĂŁo de proteĂnas mitocondriais. Este processo exige a coordenação entre as mitocĂŽndrias e o sistema de transcrição nuclear. O aumento da biogĂ©nese mitocondrial tem sido estudado no contexto de intervenção farmacolĂłgica e nĂŁo farmacolĂłgica, atravĂ©s de modificaçÔes de estilos de vida, como o exercĂcio fĂsico e restrição calĂłrica. Muitos dos moduladores abordados ao longo deste trabalho de revisĂŁo sĂŁo fĂĄrmacos com indicação para sĂndrome metabĂłlica e patologias relacionadas, e que demonstram ser benĂ©ficos em doenças neurodegenerativas e neoplĂĄsicas. O desenvolvimento de Inibidores da biogĂ©nese mitocondrial ganhou interesse e vantagens terapĂȘuticas em condiçÔes onde a proliferação destes organelos favorece mecanismos patolĂłgicos, cujo controlo e inibição sĂŁo determinantes, como sĂŁo exemplos alguns tipos de tumores.
The mitochondrion is a multi-functional organelle, playing a key role in cell survival, differentiation and death. The development of specific modulators of certain mitochondrial functions is reinforced by the disruption in mitochondrial homeostasis, evidenced by an extensive list of pathologies. Mitochondrial dysfunction is present in rare mitochondrial diseases, as a primary consequence of hereditary mutations, and in diseases acquired in a multifactorial context associated with aging, like neurodegenerative, metabolic, cardiovascular and neoplastic diseases. The events of heteroplasmy, changes in proteostasis, oxidative stress, changes in the flux of nutrients and ions such as calcium, accumulation of fragmented mitochondria, changes in the profile of transcription factors of mitochondrial biogenesis, decrease in the capacity of oxidative phosphorylation, are part of this complex set of cellular changes. In this context, the modulation of factors that regulate the mitochondrial biogenesis aims to increase the body's function by promoting the expression of mitochondrial components and, therefore, a better performance and bioenergetic adaptation, promoting celullar protection and repairing mechanisms. Mitochondrial biogenesis is regulated by a network of signaling cascades that converge in the activation of the coactivator PGC-1α, the main regulator of the process, and which results in the activation of mitochondrial transcription effectors NRF1, NRF2 and TFAM, and subsequent expression of mitochondrial proteins. This process results from coordination between the mitochondria and the nucleus transcriptional system. The increase in mitochondrial biogenesis has been studied in the context of pharmacological and non-pharmacological intervention, through lifestyle modifications such as physical exercise and caloric restriction. Many of the mitochondrial biogenesis modulators, which will be approached in the present work, are drugs with indication for metabolic syndrome and related pathologies, that have been shown to be beneficial in neurodegenerative and neoplastic diseases. The development of mitochondrial biogenesis inhibitors has gained enormous interest and therapeutic advantages in conditions where the proliferation of mitochondria favors pathological mechanisms that need to be controlled, as observed in some types of tumors.
The mitochondrion is a multi-functional organelle, playing a key role in cell survival, differentiation and death. The development of specific modulators of certain mitochondrial functions is reinforced by the disruption in mitochondrial homeostasis, evidenced by an extensive list of pathologies. Mitochondrial dysfunction is present in rare mitochondrial diseases, as a primary consequence of hereditary mutations, and in diseases acquired in a multifactorial context associated with aging, like neurodegenerative, metabolic, cardiovascular and neoplastic diseases. The events of heteroplasmy, changes in proteostasis, oxidative stress, changes in the flux of nutrients and ions such as calcium, accumulation of fragmented mitochondria, changes in the profile of transcription factors of mitochondrial biogenesis, decrease in the capacity of oxidative phosphorylation, are part of this complex set of cellular changes. In this context, the modulation of factors that regulate the mitochondrial biogenesis aims to increase the body's function by promoting the expression of mitochondrial components and, therefore, a better performance and bioenergetic adaptation, promoting celullar protection and repairing mechanisms. Mitochondrial biogenesis is regulated by a network of signaling cascades that converge in the activation of the coactivator PGC-1α, the main regulator of the process, and which results in the activation of mitochondrial transcription effectors NRF1, NRF2 and TFAM, and subsequent expression of mitochondrial proteins. This process results from coordination between the mitochondria and the nucleus transcriptional system. The increase in mitochondrial biogenesis has been studied in the context of pharmacological and non-pharmacological intervention, through lifestyle modifications such as physical exercise and caloric restriction. Many of the mitochondrial biogenesis modulators, which will be approached in the present work, are drugs with indication for metabolic syndrome and related pathologies, that have been shown to be beneficial in neurodegenerative and neoplastic diseases. The development of mitochondrial biogenesis inhibitors has gained enormous interest and therapeutic advantages in conditions where the proliferation of mitochondria favors pathological mechanisms that need to be controlled, as observed in some types of tumors.
Descrição
Trabalho Final de Mestrado Integrado, CiĂȘncias FarmacĂȘuticas, 2021, Universidade de Lisboa, Faculdade de FarmĂĄcia.
Palavras-chave
Biogénese mitocondrial PGC-1α Moduladores da biogénese mitocondrial Doenças mitocondriais Envelhecimento Mestrado integrado - 2021