Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis

Autores
Fanibunda, S. E.; Deb, Sukrita; Maniyadath, Babukrishna; Tiwari, Praachi; Ghai, Utkarsha; Gupta, Samir; Figueiredo, Dwight; Weisstaub, Noelia V.; Gingrich, Jay A.; Vaidya, Ashok D.B.; Kolthur Seetharam, Ullas; Vaidya, Vidita A.
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1–PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.
Fil: Fanibunda, S. E.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España. Kasturba Health Society; India
Fil: Deb, Sukrita. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Maniyadath, Babukrishna. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Tiwari, Praachi. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Ghai, Utkarsha. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Gupta, Samir. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Figueiredo, Dwight. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Weisstaub, Noelia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina
Fil: Gingrich, Jay A.. Columbia University; Estados Unidos
Fil: Vaidya, Ashok D.B.. Kasturba Health Society; India
Fil: Kolthur Seetharam, Ullas. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Vaidya, Vidita A.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Materia
5-HT
5-HT2A RECEPTOR
MITOCHONDRIA
NEURONAL SURVIVAL
SIRTUIN 1
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/135930
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/135930
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axisFanibunda, S. E.Deb, SukritaManiyadath, BabukrishnaTiwari, PraachiGhai, UtkarshaGupta, SamirFigueiredo, DwightWeisstaub, Noelia V.Gingrich, Jay A.Vaidya, Ashok D.B.Kolthur Seetharam, UllasVaidya, Vidita A.5-HT5-HT2A RECEPTORMITOCHONDRIANEURONAL SURVIVALSIRTUIN 1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1–PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.Fil: Fanibunda, S. E.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España. Kasturba Health Society; IndiaFil: Deb, Sukrita. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Maniyadath, Babukrishna. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Tiwari, Praachi. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Ghai, Utkarsha. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Gupta, Samir. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Figueiredo, Dwight. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Weisstaub, Noelia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Gingrich, Jay A.. Columbia University; Estados UnidosFil: Vaidya, Ashok D.B.. Kasturba Health Society; IndiaFil: Kolthur Seetharam, Ullas. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Vaidya, Vidita A.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaNational Academy of Sciences2019-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/135930Fanibunda, S. E.; Deb, Sukrita; Maniyadath, Babukrishna; Tiwari, Praachi; Ghai, Utkarsha; et al.; Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 166; 22; 5-2019; 11028-110370027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1821332116info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/116/22/11028info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:38:10Zoai:ri.conicet.gov.ar:11336/135930instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:38:10.484CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
title Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
spellingShingle Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
Fanibunda, S. E.
5-HT
5-HT2A RECEPTOR
MITOCHONDRIA
NEURONAL SURVIVAL
SIRTUIN 1
title_short Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
title_full Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
title_fullStr Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
title_full_unstemmed Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
title_sort Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis
dc.creator.none.fl_str_mv Fanibunda, S. E.
Deb, Sukrita
Maniyadath, Babukrishna
Tiwari, Praachi
Ghai, Utkarsha
Gupta, Samir
Figueiredo, Dwight
Weisstaub, Noelia V.
Gingrich, Jay A.
Vaidya, Ashok D.B.
Kolthur Seetharam, Ullas
Vaidya, Vidita A.
author Fanibunda, S. E.
author_facet Fanibunda, S. E.
Deb, Sukrita
Maniyadath, Babukrishna
Tiwari, Praachi
Ghai, Utkarsha
Gupta, Samir
Figueiredo, Dwight
Weisstaub, Noelia V.
Gingrich, Jay A.
Vaidya, Ashok D.B.
Kolthur Seetharam, Ullas
Vaidya, Vidita A.
author_role author
author2 Deb, Sukrita
Maniyadath, Babukrishna
Tiwari, Praachi
Ghai, Utkarsha
Gupta, Samir
Figueiredo, Dwight
Weisstaub, Noelia V.
Gingrich, Jay A.
Vaidya, Ashok D.B.
Kolthur Seetharam, Ullas
Vaidya, Vidita A.
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 5-HT
5-HT2A RECEPTOR
MITOCHONDRIA
NEURONAL SURVIVAL
SIRTUIN 1
topic 5-HT
5-HT2A RECEPTOR
MITOCHONDRIA
NEURONAL SURVIVAL
SIRTUIN 1
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1–PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.
Fil: Fanibunda, S. E.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España. Kasturba Health Society; India
Fil: Deb, Sukrita. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Maniyadath, Babukrishna. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Tiwari, Praachi. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Ghai, Utkarsha. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Gupta, Samir. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Figueiredo, Dwight. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Weisstaub, Noelia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina
Fil: Gingrich, Jay A.. Columbia University; Estados Unidos
Fil: Vaidya, Ashok D.B.. Kasturba Health Society; India
Fil: Kolthur Seetharam, Ullas. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
Fil: Vaidya, Vidita A.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España
description Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1–PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.
publishDate 2019
dc.date.none.fl_str_mv 2019-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/135930
Fanibunda, S. E.; Deb, Sukrita; Maniyadath, Babukrishna; Tiwari, Praachi; Ghai, Utkarsha; et al.; Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 166; 22; 5-2019; 11028-11037
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/135930
identifier_str_mv Fanibunda, S. E.; Deb, Sukrita; Maniyadath, Babukrishna; Tiwari, Praachi; Ghai, Utkarsha; et al.; Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 166; 22; 5-2019; 11028-11037
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1821332116
info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/116/22/11028
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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