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Advisor(s)
Abstract(s)
O termo “bioenergética mitocondrial” refere-se aos processos de transformação de energia que ocorrem na mitocôndria. Estes organelos estão presentes em quase todas as células do organismo humano. Uma das suas funções primordiais baseia-se na “respiração celular” e no processo de fosforilação oxidativa, que culmina com a libertação de energia sob a forma de Adenosina Trifosfato (ATP). A mitocôndria é regulada pelos genomas nuclear e mitocondrial, pelo que mutações em ambos os genomas podem estar na origem das doenças mitocondriais. Estas doenças caracterizam-se geralmente por uma deficiência ao nível da fosforilação oxidativa, e estão associadas a uma ampla variedade de sintomas clínicos, início das manifestações e sua severidade, bem como a distintas alterações moleculares e bioquímicas. O padrão de hereditariedade das doenças mitocondriais depende do genoma onde ocorre a mutação. Se ocorrer no DNA nuclear, a doença segue os padrões de hereditariedade Mendeliana. Se ocorrer no DNA mitocondrial, então a hereditariedade é exclusivamente materna, sendo que o modo como a doença é apresentada depende do nível de heteroplasmia e do efeito bottleneck que ocorre durante a oogénese.
O diagnóstico das doenças mitocondriais é dificultado pela sua heterogeneidade e inespecificidade dos seus sintomas, assim como pela raridade destas doenças. Os métodos de diagnóstico utilizados atualmente incluem análises bioquímicas e histopatológicas, estudos funcionais e testes genéticos moleculares.
Um grande desafio tem sido também o desenvolvimento de terapêuticas eficazes, pelo que para a maioria dos doentes a terapêutica é limitada ao tratamento sintomático, tentando prevenir o desenvolvimento de complicações. Uma nova estratégia terapêutica através da manipulação dos níveis de heteroplasmia de mtDNA tem apresentado resultados promissores e poderá revolucionar o tratamento e prevenção destas doenças num futuro próximo. Novas estratégias de diagnóstico direcionadas aos mecanismos de transmissão de doenças mitocondriais à descendência têm também emergido em trabalhos recentes. Estas técnicas englobam o diagnóstico pré-natal, o diagnóstico genético pré-implantação, a doação de óvulos, a doação mitocondrial e o uso de mitoTALENs e mtZNF em oócitos. Os avanços nestas áreas de intervenção e em novas terapêuticas para estas patologias genéticas, serão da maior relevância no futuro.
“Mitochondrial bioenergetics” refers to the energy transformation processes that occur in mitochondria. Mitochondria are organelles present in almost every cells of the human body. Their major role involves “cellular respiration” and the process of oxidative phosphorylation, in which energy is released in the form of ATP. Mitochondria are regulated by both nuclear and mitochondrial genomes, so mutations in both genomes can originate mitochondrial diseases. These diseases are generally characterized by a deficiency in oxidative phosphorylation, and are associated with a wide variety of clinical symptoms, onset of manifestations and their severity, as well as distinct molecular and biochemical alterations. The pattern of inheritance of mitochondrial diseases depends on the genome where the mutation occurs. If it occurs in the nuclear DNA, the disease follows Mendelian inheritance patterns. If it occurs in the mitochondrial DNA, then inheritance is exclusively maternal, and the way in which the disease is presented depends on the level of heteroplasmy and the bottleneck effect that occurs during oogenesis. The diagnosis of mitochondrial diseases is hampered by their heterogeneity and unspecified symptoms, as well as by the rarity of these diseases. Diagnostic methods currently in use include biochemical and histopathological analyses, functional studies and molecular genetic tests. A major challenge has been the development of effective therapies, therefore, for most patients, therapy is limited to the management of symptoms attempting to prevent potential complications. A new therapeutic strategy by shifting the heteroplasmy levels has shown promising results and could revolutionize the treatment and prevention of these diseases in a near future. New strategies for diagnosis have also emerged, targeting the transmission mechanisms of mitochondrial diseases to offspring. These techniques include prenatal diagnosis, preimplantation genetic diagnosis, egg donation, mitochondrial donation and the use of mitoTALENs and mtZNF in oocytes. Advances in these areas of intervention and in new therapies for these genetic pathologies will be of great relevance in the future.
“Mitochondrial bioenergetics” refers to the energy transformation processes that occur in mitochondria. Mitochondria are organelles present in almost every cells of the human body. Their major role involves “cellular respiration” and the process of oxidative phosphorylation, in which energy is released in the form of ATP. Mitochondria are regulated by both nuclear and mitochondrial genomes, so mutations in both genomes can originate mitochondrial diseases. These diseases are generally characterized by a deficiency in oxidative phosphorylation, and are associated with a wide variety of clinical symptoms, onset of manifestations and their severity, as well as distinct molecular and biochemical alterations. The pattern of inheritance of mitochondrial diseases depends on the genome where the mutation occurs. If it occurs in the nuclear DNA, the disease follows Mendelian inheritance patterns. If it occurs in the mitochondrial DNA, then inheritance is exclusively maternal, and the way in which the disease is presented depends on the level of heteroplasmy and the bottleneck effect that occurs during oogenesis. The diagnosis of mitochondrial diseases is hampered by their heterogeneity and unspecified symptoms, as well as by the rarity of these diseases. Diagnostic methods currently in use include biochemical and histopathological analyses, functional studies and molecular genetic tests. A major challenge has been the development of effective therapies, therefore, for most patients, therapy is limited to the management of symptoms attempting to prevent potential complications. A new therapeutic strategy by shifting the heteroplasmy levels has shown promising results and could revolutionize the treatment and prevention of these diseases in a near future. New strategies for diagnosis have also emerged, targeting the transmission mechanisms of mitochondrial diseases to offspring. These techniques include prenatal diagnosis, preimplantation genetic diagnosis, egg donation, mitochondrial donation and the use of mitoTALENs and mtZNF in oocytes. Advances in these areas of intervention and in new therapies for these genetic pathologies will be of great relevance in the future.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Mitocôndria Doenças mitocondriais Doação mitocondrial Bioenergética mitocondrial Mestrado integrado - 2021