Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease

Autores
Pirola, Carlos José; Garaycoechea, Martin Enrique; Flichman, Diego Martin; Castaño, Gustavo Osvaldo; Sookoian, Silvia Cristina
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and aims: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis – NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). Methods: We included 252 liver specimens of NAFLD patients – in whom histological disease ranged from mild to severe – which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal – a product of lipid peroxidation and 8-hydroxy-2’-deoxyguanosine, a marker of oxidative damage – were measured. Results: Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. Conclusion: NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Garaycoechea, Martin Enrique. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina
Fil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Materia
FIBROSIS
GENETICS
MITOCHONDRIAL DNA
MT-CYB
NASH
OXIDATIVE DAMAGE
TRANSCRIPTOME
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:11336/117932
Acceder
id CONICETDig_a4bee791d2288bae54cbfda92648edbf
oai_identifier_str oai:ri.conicet.gov.ar:11336/117932
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver diseasePirola, Carlos JoséGaraycoechea, Martin EnriqueFlichman, Diego MartinCastaño, Gustavo OsvaldoSookoian, Silvia CristinaFIBROSISGENETICSMITOCHONDRIAL DNAMT-CYBNASHOXIDATIVE DAMAGETRANSCRIPTOMEhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Background and aims: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis – NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). Methods: We included 252 liver specimens of NAFLD patients – in whom histological disease ranged from mild to severe – which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal – a product of lipid peroxidation and 8-hydroxy-2’-deoxyguanosine, a marker of oxidative damage – were measured. Results: Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. Conclusion: NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Garaycoechea, Martin Enrique. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaWiley Blackwell Publishing, Inc2020-07-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/117932Pirola, Carlos José; Garaycoechea, Martin Enrique; Flichman, Diego Martin; Castaño, Gustavo Osvaldo; Sookoian, Silvia Cristina; Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease; Wiley Blackwell Publishing, Inc; Journal Of Internal Medicine; 7-7-2020; 1-260954-6820CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13147info:eu-repo/semantics/altIdentifier/doi/10.1111/joim.13147info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:49:55Zoai:ri.conicet.gov.ar:11336/117932instacron: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:34982025-09-03 09:49:55.315CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
title Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
spellingShingle Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
Pirola, Carlos José
FIBROSIS
GENETICS
MITOCHONDRIAL DNA
MT-CYB
NASH
OXIDATIVE DAMAGE
TRANSCRIPTOME
title_short Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
title_full Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
title_fullStr Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
title_full_unstemmed Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
title_sort Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease
dc.creator.none.fl_str_mv Pirola, Carlos José
Garaycoechea, Martin Enrique
Flichman, Diego Martin
Castaño, Gustavo Osvaldo
Sookoian, Silvia Cristina
author Pirola, Carlos José
author_facet Pirola, Carlos José
Garaycoechea, Martin Enrique
Flichman, Diego Martin
Castaño, Gustavo Osvaldo
Sookoian, Silvia Cristina
author_role author
author2 Garaycoechea, Martin Enrique
Flichman, Diego Martin
Castaño, Gustavo Osvaldo
Sookoian, Silvia Cristina
author2_role author
author
author
author
dc.subject.none.fl_str_mv FIBROSIS
GENETICS
MITOCHONDRIAL DNA
MT-CYB
NASH
OXIDATIVE DAMAGE
TRANSCRIPTOME
topic FIBROSIS
GENETICS
MITOCHONDRIAL DNA
MT-CYB
NASH
OXIDATIVE DAMAGE
TRANSCRIPTOME
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background and aims: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis – NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). Methods: We included 252 liver specimens of NAFLD patients – in whom histological disease ranged from mild to severe – which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal – a product of lipid peroxidation and 8-hydroxy-2’-deoxyguanosine, a marker of oxidative damage – were measured. Results: Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. Conclusion: NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Garaycoechea, Martin Enrique. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina
Fil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
description Background and aims: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis – NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). Methods: We included 252 liver specimens of NAFLD patients – in whom histological disease ranged from mild to severe – which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal – a product of lipid peroxidation and 8-hydroxy-2’-deoxyguanosine, a marker of oxidative damage – were measured. Results: Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. Conclusion: NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.
publishDate 2020
dc.date.none.fl_str_mv 2020-07-07
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/11336/117932
Pirola, Carlos José; Garaycoechea, Martin Enrique; Flichman, Diego Martin; Castaño, Gustavo Osvaldo; Sookoian, Silvia Cristina; Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease; Wiley Blackwell Publishing, Inc; Journal Of Internal Medicine; 7-7-2020; 1-26
0954-6820
CONICET Digital
CONICET
url http://hdl.handle.net/11336/117932
identifier_str_mv Pirola, Carlos José; Garaycoechea, Martin Enrique; Flichman, Diego Martin; Castaño, Gustavo Osvaldo; Sookoian, Silvia Cristina; Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease; Wiley Blackwell Publishing, Inc; Journal Of Internal Medicine; 7-7-2020; 1-26
0954-6820
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13147
info:eu-repo/semantics/altIdentifier/doi/10.1111/joim.13147
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
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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
_version_ 1842269001400451072
score 12.885934

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