Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II

Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized...

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Detalles Bibliográficos
Autores: Siendones, Emilio, Ballesteros, Manuel, Navas, Plácido
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/242276
Acceso en línea:http://hdl.handle.net/10261/242276
Access Level:acceso abierto
Palabra clave:Diaphorase
CYB5R3
Methaemoglobinaemia etiology
NAD+ depletion
NAD(P)H oxidase
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spelling Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type IISiendones, EmilioBallesteros, ManuelNavas, PlácidoDiaphoraseCYB5R3Methaemoglobinaemia etiologyNAD+ depletionNAD(P)H oxidaseCytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD+/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism.This work has been funded by the Instituto de Salud Carlos III FIS PI17-01286 grant. Authors were also funded by the Andalusian Government BIO177 research group.Multidisciplinary Digital Publishing InstituteInstituto de Salud Carlos IIIJunta de AndalucíaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120182021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/242276reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.3390/jcm7100341Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2422762026-05-22T06:33:51Z
dc.title.none.fl_str_mv Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
title Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
spellingShingle Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
Siendones, Emilio
Diaphorase
CYB5R3
Methaemoglobinaemia etiology
NAD+ depletion
NAD(P)H oxidase
title_short Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
title_full Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
title_fullStr Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
title_full_unstemmed Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
title_sort Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II
dc.creator.none.fl_str_mv Siendones, Emilio
Ballesteros, Manuel
Navas, Plácido
author Siendones, Emilio
author_facet Siendones, Emilio
Ballesteros, Manuel
Navas, Plácido
author_role author
author2 Ballesteros, Manuel
Navas, Plácido
author2_role author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Junta de Andalucía
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Diaphorase
CYB5R3
Methaemoglobinaemia etiology
NAD+ depletion
NAD(P)H oxidase
topic Diaphorase
CYB5R3
Methaemoglobinaemia etiology
NAD+ depletion
NAD(P)H oxidase
description Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD+/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism.
publishDate 2018
dc.date.none.fl_str_mv 2018
2021
2021
2021
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/10261/242276
url http://hdl.handle.net/10261/242276
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.3390/jcm7100341
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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
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