Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency

Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutatio...

Descripción completa

Detalles Bibliográficos
Autores: Al Khazal, Fatimah, Kang, Seungwo, Nelson Holte, Molly, Choi, Doo-Sup, Singh, Ravinder, Ortega-Sáenz, Patricia, López-Barneo, José, Maher III, L. James
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/265971
Acceso en línea:http://hdl.handle.net/10261/265971
Access Level:acceso abierto
Palabra clave:Catecholamines
Dopaminergic cells
Familial paraganglioma
Mouse
Mitochondrial diseases
Obesity
Succinate dehydrogenase
Tyrosine hydroxylase
id ES_d8aad75c2188e0193bb38703cb7befb2
oai_identifier_str oai:digital.csic.es:10261/265971
network_acronym_str ES
network_name_str España
repository_id_str
spelling Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiencyAl Khazal, FatimahKang, SeungwoNelson Holte, MollyChoi, Doo-SupSingh, RavinderOrtega-Sáenz, PatriciaLópez-Barneo, JoséMaher III, L. JamesCatecholaminesDopaminergic cellsFamilial paragangliomaMouseMitochondrial diseasesObesitySuccinate dehydrogenaseTyrosine hydroxylaseMutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH+ glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH+ cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.This work was supported by the Mayo Clinic, the Paradifference Foundation (LJM), National Institute on Alcohol Abuse and Alcoholism (K01 AA027773 to SK, R01 AA018779 to DSC). PO-S and JL-B are supported by grants from the Spanish Ministries of Science and Innovation and Health (SAF2016-74990-R) and the European Research Council (ERC-ADGPRJ201502629), The technical assistance of Daniel Lindberg is acknowledged.John Wiley & SonsMayo ClinicParadifference FoundationNational Institute on Alcohol Abuse and Alcoholism (US)Ministerio de Ciencia e Innovación (España)European Research CouncilConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/265971reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#SAF2016-74990-Rhttp://dx.doi.org/10.1096/fj.202002100RSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2659712026-05-22T06:33:51Z
dc.title.none.fl_str_mv Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
title Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
spellingShingle Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
Al Khazal, Fatimah
Catecholamines
Dopaminergic cells
Familial paraganglioma
Mouse
Mitochondrial diseases
Obesity
Succinate dehydrogenase
Tyrosine hydroxylase
title_short Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
title_full Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
title_fullStr Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
title_full_unstemmed Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
title_sort Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
dc.creator.none.fl_str_mv Al Khazal, Fatimah
Kang, Seungwo
Nelson Holte, Molly
Choi, Doo-Sup
Singh, Ravinder
Ortega-Sáenz, Patricia
López-Barneo, José
Maher III, L. James
author Al Khazal, Fatimah
author_facet Al Khazal, Fatimah
Kang, Seungwo
Nelson Holte, Molly
Choi, Doo-Sup
Singh, Ravinder
Ortega-Sáenz, Patricia
López-Barneo, José
Maher III, L. James
author_role author
author2 Kang, Seungwo
Nelson Holte, Molly
Choi, Doo-Sup
Singh, Ravinder
Ortega-Sáenz, Patricia
López-Barneo, José
Maher III, L. James
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Mayo Clinic
Paradifference Foundation
National Institute on Alcohol Abuse and Alcoholism (US)
Ministerio de Ciencia e Innovación (España)
European Research Council
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Catecholamines
Dopaminergic cells
Familial paraganglioma
Mouse
Mitochondrial diseases
Obesity
Succinate dehydrogenase
Tyrosine hydroxylase
topic Catecholamines
Dopaminergic cells
Familial paraganglioma
Mouse
Mitochondrial diseases
Obesity
Succinate dehydrogenase
Tyrosine hydroxylase
description Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH+ glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH+ cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/265971
url http://hdl.handle.net/10261/265971
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
SAF2016-74990-R
http://dx.doi.org/10.1096/fj.202002100R
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869421194406526976
score 15,812429

Similares en LA Referencia