Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/23872 |
Resumo: | Neurogenesis occurs throughout life in discrete areas of the adult mammalian brain. Unfortunately, there is a lack of effective regeneration during aging or after injury. Therefore, life-long potentiation of endogenous neurogenesis represents a major issue. Curiously, proliferation and differentiation potential of neural stem cells (NSCs) were recently shown to be highly dependent on mitochondrial bioenergetics and fatty acid (FA) lipogenesis. Furthermore, tauroursodeoxycholic acid (TUDCA), an endogenous neuroprotective bile acid, considered a regulator of energy metabolism and an inhibitor of early differentiation-associated apoptosis events in NSCs, stimulates proliferation and neuronal conversion of these cells. We aimed to clarify the impact of TUDCA on the mitochondrial proteome in self-renewing or differentiating mouse NSCs, using liquid chromatography coupled with mass spectrometry (LC-MS) based detection of differential proteomics. Validation of mitochondrial proteomic analysis by Western blot in two different NSC lines revealed that TUDCA significantly decreases the mitochondrial levels of long-chain acyl-CoA dehydrogenase (LCAD) protein upon differentiation, an enzyme crucial for β-oxidation of long-chain FAs. Further, nuclear levels of sterol regulatory element-binding protein (SREBP-1), a major transcription factor of lipid biosynthesis, were also found significantly increased, as the levels of palmitic and stearic FAs raise up. Interestingly, mitochondrial levels of pyruvate dehydrogenase E1-α (PDHE1-α), an enzymatic subunit belonging to glucose metabolism, were also markedly enhanced by TUDCA. Of note, TUDCA promoted mitochondria-nucleus translocation of PDHE1-α. Therefore, the proliferative role of this bile acid may rely, in part, in increasing the pool of mitochondrial and/or nuclear acetyl-CoA to assure NSC cycle progression. Finally, LCAD, SREBP-1, and PDHE1-α expression profiles were also assessed during early stages of neural differentiation bringing novel insights to NSC metabolic choices throughout differentiation. Altogether, our results unravel the metabolic impact of TUDCA in controlling NSC fate, demonstrating that this bile acid not only induces mitochondrial advantageous conditions but also metabolic plasticity. |
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Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell ProliferationDifferentiationLipid metabolismMitochondriaNeural stem cellsProliferationTauroursodeoxycholic acidDomínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e TecnologiasNeurogenesis occurs throughout life in discrete areas of the adult mammalian brain. Unfortunately, there is a lack of effective regeneration during aging or after injury. Therefore, life-long potentiation of endogenous neurogenesis represents a major issue. Curiously, proliferation and differentiation potential of neural stem cells (NSCs) were recently shown to be highly dependent on mitochondrial bioenergetics and fatty acid (FA) lipogenesis. Furthermore, tauroursodeoxycholic acid (TUDCA), an endogenous neuroprotective bile acid, considered a regulator of energy metabolism and an inhibitor of early differentiation-associated apoptosis events in NSCs, stimulates proliferation and neuronal conversion of these cells. We aimed to clarify the impact of TUDCA on the mitochondrial proteome in self-renewing or differentiating mouse NSCs, using liquid chromatography coupled with mass spectrometry (LC-MS) based detection of differential proteomics. Validation of mitochondrial proteomic analysis by Western blot in two different NSC lines revealed that TUDCA significantly decreases the mitochondrial levels of long-chain acyl-CoA dehydrogenase (LCAD) protein upon differentiation, an enzyme crucial for β-oxidation of long-chain FAs. Further, nuclear levels of sterol regulatory element-binding protein (SREBP-1), a major transcription factor of lipid biosynthesis, were also found significantly increased, as the levels of palmitic and stearic FAs raise up. Interestingly, mitochondrial levels of pyruvate dehydrogenase E1-α (PDHE1-α), an enzymatic subunit belonging to glucose metabolism, were also markedly enhanced by TUDCA. Of note, TUDCA promoted mitochondria-nucleus translocation of PDHE1-α. Therefore, the proliferative role of this bile acid may rely, in part, in increasing the pool of mitochondrial and/or nuclear acetyl-CoA to assure NSC cycle progression. Finally, LCAD, SREBP-1, and PDHE1-α expression profiles were also assessed during early stages of neural differentiation bringing novel insights to NSC metabolic choices throughout differentiation. Altogether, our results unravel the metabolic impact of TUDCA in controlling NSC fate, demonstrating that this bile acid not only induces mitochondrial advantageous conditions but also metabolic plasticity.Solá, SusanaRodrigues, CecíliaRUNFernandes, Marta Sofia Barbosa2019-10-01T00:30:32Z2017-092017-092017-09-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/23872enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:12:17Zoai:run.unl.pt:10362/23872Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:27:55.855064Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation |
title |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation |
spellingShingle |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation Fernandes, Marta Sofia Barbosa Differentiation Lipid metabolism Mitochondria Neural stem cells Proliferation Tauroursodeoxycholic acid Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
title_short |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation |
title_full |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation |
title_fullStr |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation |
title_full_unstemmed |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation |
title_sort |
Tauroursodeoxycholic Acid Drives Mitochondrial Bioenergetics Toward Neural Stem Cell Proliferation |
author |
Fernandes, Marta Sofia Barbosa |
author_facet |
Fernandes, Marta Sofia Barbosa |
author_role |
author |
dc.contributor.none.fl_str_mv |
Solá, Susana Rodrigues, Cecília RUN |
dc.contributor.author.fl_str_mv |
Fernandes, Marta Sofia Barbosa |
dc.subject.por.fl_str_mv |
Differentiation Lipid metabolism Mitochondria Neural stem cells Proliferation Tauroursodeoxycholic acid Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
topic |
Differentiation Lipid metabolism Mitochondria Neural stem cells Proliferation Tauroursodeoxycholic acid Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
description |
Neurogenesis occurs throughout life in discrete areas of the adult mammalian brain. Unfortunately, there is a lack of effective regeneration during aging or after injury. Therefore, life-long potentiation of endogenous neurogenesis represents a major issue. Curiously, proliferation and differentiation potential of neural stem cells (NSCs) were recently shown to be highly dependent on mitochondrial bioenergetics and fatty acid (FA) lipogenesis. Furthermore, tauroursodeoxycholic acid (TUDCA), an endogenous neuroprotective bile acid, considered a regulator of energy metabolism and an inhibitor of early differentiation-associated apoptosis events in NSCs, stimulates proliferation and neuronal conversion of these cells. We aimed to clarify the impact of TUDCA on the mitochondrial proteome in self-renewing or differentiating mouse NSCs, using liquid chromatography coupled with mass spectrometry (LC-MS) based detection of differential proteomics. Validation of mitochondrial proteomic analysis by Western blot in two different NSC lines revealed that TUDCA significantly decreases the mitochondrial levels of long-chain acyl-CoA dehydrogenase (LCAD) protein upon differentiation, an enzyme crucial for β-oxidation of long-chain FAs. Further, nuclear levels of sterol regulatory element-binding protein (SREBP-1), a major transcription factor of lipid biosynthesis, were also found significantly increased, as the levels of palmitic and stearic FAs raise up. Interestingly, mitochondrial levels of pyruvate dehydrogenase E1-α (PDHE1-α), an enzymatic subunit belonging to glucose metabolism, were also markedly enhanced by TUDCA. Of note, TUDCA promoted mitochondria-nucleus translocation of PDHE1-α. Therefore, the proliferative role of this bile acid may rely, in part, in increasing the pool of mitochondrial and/or nuclear acetyl-CoA to assure NSC cycle progression. Finally, LCAD, SREBP-1, and PDHE1-α expression profiles were also assessed during early stages of neural differentiation bringing novel insights to NSC metabolic choices throughout differentiation. Altogether, our results unravel the metabolic impact of TUDCA in controlling NSC fate, demonstrating that this bile acid not only induces mitochondrial advantageous conditions but also metabolic plasticity. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-09 2017-09 2017-09-01T00:00:00Z 2019-10-01T00:30:32Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/23872 |
url |
http://hdl.handle.net/10362/23872 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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