Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.

The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransfe...

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Authors: Piroli, Gerardo G, Manuel, Allison M, McCain, Richard S, Smith, Holland H, Ozohanics, Oliver, Mellid, Sara, Cox, J Hunter, Cotham, William E, Walla, Michael D, Cascon Soriano, Alberto, Ambrus, Attila, Frizzell, Norma
Format: article
Publication Date:2023
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26050
Online Access:https://hdl.handle.net/20.500.12105/26050
Access Level:Open access
Keyword:Alpha-ketoglutarate dehydrogenase
Complex I
Fumarate
Leigh syndrome
Protein succination
Substrate level phosphorylation
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spelling Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.Piroli, Gerardo GManuel, Allison MMcCain, Richard SSmith, Holland HOzohanics, OliverMellid, SaraCox, J HunterCotham, William EWalla, Michael DCascon Soriano, AlbertoAmbrus, AttilaFrizzell, NormaAlpha-ketoglutarate dehydrogenaseComplex IFumarateLeigh syndromeProtein succinationSubstrate level phosphorylationThe NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.ElsevierUnited States Department of Health & Human Services National Institutes of Health (NIH) - USANational Science Foundation (NSF)Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA)Ministry of Innovation and Technology of HungaryInstituto de Salud Carlos III20252025-01-1720232023-11-0120232023-11-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.12105/26050reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023 PI22%2F01490 Identificación de nuevos genes de susceptibilidad en paragangliomas de cabeza y cuello mediante perfiles transcriptómicos y secuenciación del genoma completoopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/260502026-06-12T12:43:37Z
dc.title.none.fl_str_mv Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
title Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
spellingShingle Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
Piroli, Gerardo G
Alpha-ketoglutarate dehydrogenase
Complex I
Fumarate
Leigh syndrome
Protein succination
Substrate level phosphorylation
title_short Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
title_full Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
title_fullStr Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
title_full_unstemmed Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
title_sort Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
dc.creator.none.fl_str_mv Piroli, Gerardo G
Manuel, Allison M
McCain, Richard S
Smith, Holland H
Ozohanics, Oliver
Mellid, Sara
Cox, J Hunter
Cotham, William E
Walla, Michael D
Cascon Soriano, Alberto
Ambrus, Attila
Frizzell, Norma
author Piroli, Gerardo G
author_facet Piroli, Gerardo G
Manuel, Allison M
McCain, Richard S
Smith, Holland H
Ozohanics, Oliver
Mellid, Sara
Cox, J Hunter
Cotham, William E
Walla, Michael D
Cascon Soriano, Alberto
Ambrus, Attila
Frizzell, Norma
author_role author
author2 Manuel, Allison M
McCain, Richard S
Smith, Holland H
Ozohanics, Oliver
Mellid, Sara
Cox, J Hunter
Cotham, William E
Walla, Michael D
Cascon Soriano, Alberto
Ambrus, Attila
Frizzell, Norma
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv United States Department of Health & Human Services National Institutes of Health (NIH) - USA
National Science Foundation (NSF)
Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA)
Ministry of Innovation and Technology of Hungary
Instituto de Salud Carlos III
dc.subject.none.fl_str_mv Alpha-ketoglutarate dehydrogenase
Complex I
Fumarate
Leigh syndrome
Protein succination
Substrate level phosphorylation
topic Alpha-ketoglutarate dehydrogenase
Complex I
Fumarate
Leigh syndrome
Protein succination
Substrate level phosphorylation
description The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-11-01
2023
2023-11-01
2025
2025-01-17
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/26050
url https://hdl.handle.net/20.500.12105/26050
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023 PI22%2F01490 Identificación de nuevos genes de susceptibilidad en paragangliomas de cabeza y cuello mediante perfiles transcriptómicos y secuenciación del genoma completo
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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