Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/103784 https://doi.org/10.1186/s12915-021-00979-5 |
Resumo: | Background: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential. Results: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein. Conclusion: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases. |
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Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum couplingHigh-throughput screenMitochondriaLuteolinMitochondria-ER contactsMitochondrial calciumAnimalsCell Line, TumorDrug Evaluation, PreclinicalEndoplasmic ReticulumHigh-Throughput Screening AssaysHumansLuteolinMiceMitochondriaNeuronsSignal TransductionBackground: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential. Results: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein. Conclusion: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases.Springer Nature2021-03-24info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/103784http://hdl.handle.net/10316/103784https://doi.org/10.1186/s12915-021-00979-5eng1741-7007Naia, Luana CarvalhoPinho, Catarina M.Dentoni, GiacomoLiu, JianpingLeal, Nuno SantosFerreira, Duarte M. S.Schreiner, BernadetteFiladi, RiccardoFão, LígiaConnolly, Niamh M. C.Forsell, PontusNordvall, GunnarShimozawa, MakotoGreotti, ElisaBasso, EmyTheurey, PierreGioran, AnnaJoselin, AlvinArsenian-Henriksson, MarieNilsson, PerRego, A. CristinaRuas, Jorge L.Park, DavidBano, DanielePizzo, PaolaPrehn, Jochen H. M.Ankarcrona, Mariainfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-11-28T21:38:53Zoai:estudogeral.uc.pt:10316/103784Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:20:33.590752Repositório 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 |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling |
title |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling |
spellingShingle |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling Naia, Luana Carvalho High-throughput screen Mitochondria Luteolin Mitochondria-ER contacts Mitochondrial calcium Animals Cell Line, Tumor Drug Evaluation, Preclinical Endoplasmic Reticulum High-Throughput Screening Assays Humans Luteolin Mice Mitochondria Neurons Signal Transduction |
title_short |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling |
title_full |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling |
title_fullStr |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling |
title_full_unstemmed |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling |
title_sort |
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling |
author |
Naia, Luana Carvalho |
author_facet |
Naia, Luana Carvalho Pinho, Catarina M. Dentoni, Giacomo Liu, Jianping Leal, Nuno Santos Ferreira, Duarte M. S. Schreiner, Bernadette Filadi, Riccardo Fão, Lígia Connolly, Niamh M. C. Forsell, Pontus Nordvall, Gunnar Shimozawa, Makoto Greotti, Elisa Basso, Emy Theurey, Pierre Gioran, Anna Joselin, Alvin Arsenian-Henriksson, Marie Nilsson, Per Rego, A. Cristina Ruas, Jorge L. Park, David Bano, Daniele Pizzo, Paola Prehn, Jochen H. M. Ankarcrona, Maria |
author_role |
author |
author2 |
Pinho, Catarina M. Dentoni, Giacomo Liu, Jianping Leal, Nuno Santos Ferreira, Duarte M. S. Schreiner, Bernadette Filadi, Riccardo Fão, Lígia Connolly, Niamh M. C. Forsell, Pontus Nordvall, Gunnar Shimozawa, Makoto Greotti, Elisa Basso, Emy Theurey, Pierre Gioran, Anna Joselin, Alvin Arsenian-Henriksson, Marie Nilsson, Per Rego, A. Cristina Ruas, Jorge L. Park, David Bano, Daniele Pizzo, Paola Prehn, Jochen H. M. Ankarcrona, Maria |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Naia, Luana Carvalho Pinho, Catarina M. Dentoni, Giacomo Liu, Jianping Leal, Nuno Santos Ferreira, Duarte M. S. Schreiner, Bernadette Filadi, Riccardo Fão, Lígia Connolly, Niamh M. C. Forsell, Pontus Nordvall, Gunnar Shimozawa, Makoto Greotti, Elisa Basso, Emy Theurey, Pierre Gioran, Anna Joselin, Alvin Arsenian-Henriksson, Marie Nilsson, Per Rego, A. Cristina Ruas, Jorge L. Park, David Bano, Daniele Pizzo, Paola Prehn, Jochen H. M. Ankarcrona, Maria |
dc.subject.por.fl_str_mv |
High-throughput screen Mitochondria Luteolin Mitochondria-ER contacts Mitochondrial calcium Animals Cell Line, Tumor Drug Evaluation, Preclinical Endoplasmic Reticulum High-Throughput Screening Assays Humans Luteolin Mice Mitochondria Neurons Signal Transduction |
topic |
High-throughput screen Mitochondria Luteolin Mitochondria-ER contacts Mitochondrial calcium Animals Cell Line, Tumor Drug Evaluation, Preclinical Endoplasmic Reticulum High-Throughput Screening Assays Humans Luteolin Mice Mitochondria Neurons Signal Transduction |
description |
Background: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential. Results: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein. Conclusion: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-03-24 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/103784 http://hdl.handle.net/10316/103784 https://doi.org/10.1186/s12915-021-00979-5 |
url |
http://hdl.handle.net/10316/103784 https://doi.org/10.1186/s12915-021-00979-5 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1741-7007 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Springer Nature |
publisher.none.fl_str_mv |
Springer Nature |
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 |
reponame_str |
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 |
repository.mail.fl_str_mv |
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1799134097831886848 |