Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

Abstract Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD contin...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Fernando Bartolome, Noemi Esteras, Angeles Martin-Requero, Claire Boutoleau-Bretonniere, Martine Vercelletto, Audrey Gabelle, Isabelle Le Ber, Tadashi Honda, Albena T. Dinkova-Kostova, John Hardy, Eva Carro, Andrey Y. Abramov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6c3d41bcb5fa43bfac86e75704ab5618
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6c3d41bcb5fa43bfac86e75704ab5618
record_format	dspace
spelling	oai:doaj.org-article:6c3d41bcb5fa43bfac86e75704ab56182021-12-02T12:32:14ZPathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates10.1038/s41598-017-01678-42045-2322https://doaj.org/article/6c3d41bcb5fa43bfac86e75704ab56182017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01678-4https://doaj.org/toc/2045-2322Abstract Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency.Fernando BartolomeNoemi EsterasAngeles Martin-RequeroClaire Boutoleau-BretonniereMartine VercellettoAudrey GabelleIsabelle Le BerTadashi HondaAlbena T. Dinkova-KostovaJohn HardyEva CarroAndrey Y. AbramovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fernando Bartolome Noemi Esteras Angeles Martin-Requero Claire Boutoleau-Bretonniere Martine Vercelletto Audrey Gabelle Isabelle Le Ber Tadashi Honda Albena T. Dinkova-Kostova John Hardy Eva Carro Andrey Y. Abramov Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
description	Abstract Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency.
format	article
author	Fernando Bartolome Noemi Esteras Angeles Martin-Requero Claire Boutoleau-Bretonniere Martine Vercelletto Audrey Gabelle Isabelle Le Ber Tadashi Honda Albena T. Dinkova-Kostova John Hardy Eva Carro Andrey Y. Abramov
author_facet	Fernando Bartolome Noemi Esteras Angeles Martin-Requero Claire Boutoleau-Bretonniere Martine Vercelletto Audrey Gabelle Isabelle Le Ber Tadashi Honda Albena T. Dinkova-Kostova John Hardy Eva Carro Andrey Y. Abramov
author_sort	Fernando Bartolome
title	Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
title_short	Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
title_full	Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
title_fullStr	Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
title_full_unstemmed	Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
title_sort	pathogenic p62/sqstm1 mutations impair energy metabolism through limitation of mitochondrial substrates
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6c3d41bcb5fa43bfac86e75704ab5618
work_keys_str_mv	AT fernandobartolome pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT noemiesteras pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT angelesmartinrequero pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT claireboutoleaubretonniere pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT martinevercelletto pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT audreygabelle pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT isabelleleber pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT tadashihonda pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT albenatdinkovakostova pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT johnhardy pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT evacarro pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates AT andreyyabramov pathogenicp62sqstm1mutationsimpairenergymetabolismthroughlimitationofmitochondrialsubstrates
_version_	1718394163418890240

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

Ejemplares similares