Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling

Detalhes bibliográficos
Autor(a) principal: Naia, Luana Carvalho
Data de Publicação: 2021
Outros Autores: 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
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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spelling 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 reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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