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Targeting mitochondria-nucleus communication to improve aging-impaired neurogenesis
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Resumo(s)
Apesar da neurogénese ocorrer em áreas restritas do cérebro adulto dos mamíferos, o seu declínio ao longo da vida tem sido sugerido como um fator importante para a diminuição das capacidades cognitivas comumente associadas ao envelhecimento. Dados recentes sugerem que a mitocôndria afeta a capacidade proliferativa e de diferenciação das células estaminais neurais (NSCs), apesar do mecanismo molecular subjacente permanecer desconhecido. Alterações na comunicação mitocôndria-núcleo são hipotéticas responsáveis pelo declínio da neurogénese no adulto. A sirtuina 3 (SIRT3), membro mitocondrial da família das sirtuinas, composta por proteínas com atividade de desacetilase, tem sido descrita como um regulador central da manutenção da atividade mitocondrial, influenciando tanto o metabolismo como o stress oxidativo da mitocôndria. Este estudo pretendeu explorar a forma como o metabolismo e o stress oxidativo da mitocôndria regulam a atividade telomérica e o destino das NSCs em condições associadas ao envelhecimento. Os resultados demonstraram que a sobre-expressão da SIRT3 reverte as alterações ao nível do potencial de diferenciação das NSCs previamente tratadas com tert-butil-hidroperóxido (tBHP), um indutor de envelhecimento celular. Concomitantemente, observou-se um aumento da desacetilação e consequente ativação da superóxido dismutase 2 (SOD2), contribuindo potencialmente para a redução do stress oxidativo das NSCs. Adicionalmente, a sobre-expressão da SIRT3 pareceu exercer um impacto positivo na atividade da transcriptase reversa da telomerase (TERT). Por outro lado, a redução da expressão da Acil-coenzima A desidrogenase de cadeia longa (LCAD), uma enzima chave na β-oxidação mitocondrial, reduziu o stress oxidativo e aumentou a capacidade proliferativa das NSCs, assim como o seu potencial estaminal. Estudos futuros deverão clarificar de que forma múltiplos fatores mitocondriais contribuem para o declínio da neurogénese associado à idade.
No geral, estes resultados reforçam a importância da atividade mitocondrial na regulação das funções nucleares, sugerindo o envolvimento da comunicação mitocôndria-núcleo na regulação da neurogénese e manutenção das NSCs. Deste modo, a modulação do estado oxidativo e do metabolismo mitocondrial parecem estratégias lógicas para influenciar o destino das NSCs e contribuir para atrasar o declínio da neurogénese associado à idade.
Despite the fact that neurogenesis occurs in discrete areas of the adult mammalian brain, age-associated decline of adult neurogenesis has been suggested as an important factor for ageing-associated cognitive impairment and neurodegeneration. Recent evidence suggests that mitochondria affect the proliferative and differentiation potential of neural stem cells (NSCs), although the underlying molecular mechanisms are still poorly understood. It is possible that the impairment of specific mitochondria-nucleus communication events may partially be responsible for the decline of adult neurogenesis and NSC plasticity. A mitochondrial member of the sirtuin family of protein deacetylases, Sirtuin 3 (SIRT3), has been described as a central player of mitochondrial biology, thus influencing mitochondrial metabolism and oxidative state. Herein, we aimed to further understand how mitochondria metabolism and oxidative stress regulate telomerase activity and NSC fate under ageing mimicked conditions. Results demonstrated that SIRT3 overexpression reverts changes in differentiation and stemness potential of NSCs treated with tert-butyl hydroperoxide (tBHP), an inducer of chronical ageing. This modulation occurred concomitantly with an increase in superoxide dismutase 2 (SOD2)-deacetylase activation, potentially reducing the oxidative stress of NSCs, and a positive impact in telomerase reverse transcriptase (TERT) activity. Additionally, reduction of long chain acyl-coenzyme A dehydrogenase (LCAD) expression, a key enzyme in mitochondrial β-oxidation, reduced oxidative stress and enhanced NSC proliferation and stemness. Future studies are needed to clarify how multiple mitochondrial factors contribute to age-related decline of neurogenesis. Overall, our results reinforce the relevance of mitochondrial activity in influencing nuclear function, indicating that the mitochondria-nucleus communication is involved in neurogenic regulation and maintenance of the NSC pool. Therefore, targeting mitochondrial oxidative state and metabolism seems a potential strategy to influence NSC fate decisions, counteract the age-related decline of neurogenesis and possibly delay ageing-associated cognitive impairment.
Despite the fact that neurogenesis occurs in discrete areas of the adult mammalian brain, age-associated decline of adult neurogenesis has been suggested as an important factor for ageing-associated cognitive impairment and neurodegeneration. Recent evidence suggests that mitochondria affect the proliferative and differentiation potential of neural stem cells (NSCs), although the underlying molecular mechanisms are still poorly understood. It is possible that the impairment of specific mitochondria-nucleus communication events may partially be responsible for the decline of adult neurogenesis and NSC plasticity. A mitochondrial member of the sirtuin family of protein deacetylases, Sirtuin 3 (SIRT3), has been described as a central player of mitochondrial biology, thus influencing mitochondrial metabolism and oxidative state. Herein, we aimed to further understand how mitochondria metabolism and oxidative stress regulate telomerase activity and NSC fate under ageing mimicked conditions. Results demonstrated that SIRT3 overexpression reverts changes in differentiation and stemness potential of NSCs treated with tert-butyl hydroperoxide (tBHP), an inducer of chronical ageing. This modulation occurred concomitantly with an increase in superoxide dismutase 2 (SOD2)-deacetylase activation, potentially reducing the oxidative stress of NSCs, and a positive impact in telomerase reverse transcriptase (TERT) activity. Additionally, reduction of long chain acyl-coenzyme A dehydrogenase (LCAD) expression, a key enzyme in mitochondrial β-oxidation, reduced oxidative stress and enhanced NSC proliferation and stemness. Future studies are needed to clarify how multiple mitochondrial factors contribute to age-related decline of neurogenesis. Overall, our results reinforce the relevance of mitochondrial activity in influencing nuclear function, indicating that the mitochondria-nucleus communication is involved in neurogenic regulation and maintenance of the NSC pool. Therefore, targeting mitochondrial oxidative state and metabolism seems a potential strategy to influence NSC fate decisions, counteract the age-related decline of neurogenesis and possibly delay ageing-associated cognitive impairment.
Descrição
Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2018
Palavras-chave
Ageing Lipid metabolism Mitochondria-nucleus cross-talk Neural stem cells Oxidative stress Teses de mestrado - 2018