Cargando…

Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG

Congenital disorders of glycosylation (CDG) and mitochondrial disorders are multisystem disorders with overlapping symptomatology. Pathogenic variants in the PMM2 gene lead to abnormal N-linked glycosylation. This disruption in glycosylation can induce endoplasmic reticulum stress, contributing to t...

Descripción completa

Detalles Bibliográficos
Autores principales: Ligezka, Anna N., Budhraja, Rohit, Nishiyama, Yurika, Fiesel, Fabienne C., Preston, Graeme, Edmondson, Andrew, Ranatunga, Wasantha, Van Hove, Johan L. K., Watzlawik, Jens O., Springer, Wolfdieter, Pandey, Akhilesh, Morava, Eva, Kozicz, Tamas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454768/
https://www.ncbi.nlm.nih.gov/pubmed/37628636
http://dx.doi.org/10.3390/genes14081585
_version_ 1785096278592454656
author Ligezka, Anna N.
Budhraja, Rohit
Nishiyama, Yurika
Fiesel, Fabienne C.
Preston, Graeme
Edmondson, Andrew
Ranatunga, Wasantha
Van Hove, Johan L. K.
Watzlawik, Jens O.
Springer, Wolfdieter
Pandey, Akhilesh
Morava, Eva
Kozicz, Tamas
author_facet Ligezka, Anna N.
Budhraja, Rohit
Nishiyama, Yurika
Fiesel, Fabienne C.
Preston, Graeme
Edmondson, Andrew
Ranatunga, Wasantha
Van Hove, Johan L. K.
Watzlawik, Jens O.
Springer, Wolfdieter
Pandey, Akhilesh
Morava, Eva
Kozicz, Tamas
author_sort Ligezka, Anna N.
collection PubMed
description Congenital disorders of glycosylation (CDG) and mitochondrial disorders are multisystem disorders with overlapping symptomatology. Pathogenic variants in the PMM2 gene lead to abnormal N-linked glycosylation. This disruption in glycosylation can induce endoplasmic reticulum stress, contributing to the disease pathology. Although impaired mitochondrial dysfunction has been reported in some CDG, cellular bioenergetics has never been evaluated in detail in PMM2-CDG. This prompted us to evaluate mitochondrial function and autophagy/mitophagy in vitro in PMM2 patient-derived fibroblast lines of differing genotypes from our natural history study. We found secondary mitochondrial dysfunction in PMM2-CDG. This dysfunction was evidenced by decreased mitochondrial maximal and ATP-linked respiration, as well as decreased complex I function of the mitochondrial electron transport chain. Our study also revealed altered autophagy in PMM2-CDG patient-derived fibroblast lines. This was marked by an increased abundance of the autophagosome marker LC3-II. Additionally, changes in the abundance and glycosylation of proteins in the autophagy and mitophagy pathways further indicated dysregulation of these cellular processes. Interestingly, serum sorbitol levels (a biomarker of disease severity) and the CDG severity score showed an inverse correlation with the abundance of the autophagosome marker LC3-II. This suggests that autophagy may act as a modulator of biochemical and clinical markers of disease severity in PMM2-CDG. Overall, our research sheds light on the complex interplay between glycosylation, mitochondrial function, and autophagy/mitophagy in PMM2-CDG. Manipulating mitochondrial dysfunction and alterations in autophagy/mitophagy pathways could offer therapeutic benefits when combined with existing treatments for PMM2-CDG.
format Online
Article
Text
id pubmed-10454768
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-104547682023-08-26 Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG Ligezka, Anna N. Budhraja, Rohit Nishiyama, Yurika Fiesel, Fabienne C. Preston, Graeme Edmondson, Andrew Ranatunga, Wasantha Van Hove, Johan L. K. Watzlawik, Jens O. Springer, Wolfdieter Pandey, Akhilesh Morava, Eva Kozicz, Tamas Genes (Basel) Article Congenital disorders of glycosylation (CDG) and mitochondrial disorders are multisystem disorders with overlapping symptomatology. Pathogenic variants in the PMM2 gene lead to abnormal N-linked glycosylation. This disruption in glycosylation can induce endoplasmic reticulum stress, contributing to the disease pathology. Although impaired mitochondrial dysfunction has been reported in some CDG, cellular bioenergetics has never been evaluated in detail in PMM2-CDG. This prompted us to evaluate mitochondrial function and autophagy/mitophagy in vitro in PMM2 patient-derived fibroblast lines of differing genotypes from our natural history study. We found secondary mitochondrial dysfunction in PMM2-CDG. This dysfunction was evidenced by decreased mitochondrial maximal and ATP-linked respiration, as well as decreased complex I function of the mitochondrial electron transport chain. Our study also revealed altered autophagy in PMM2-CDG patient-derived fibroblast lines. This was marked by an increased abundance of the autophagosome marker LC3-II. Additionally, changes in the abundance and glycosylation of proteins in the autophagy and mitophagy pathways further indicated dysregulation of these cellular processes. Interestingly, serum sorbitol levels (a biomarker of disease severity) and the CDG severity score showed an inverse correlation with the abundance of the autophagosome marker LC3-II. This suggests that autophagy may act as a modulator of biochemical and clinical markers of disease severity in PMM2-CDG. Overall, our research sheds light on the complex interplay between glycosylation, mitochondrial function, and autophagy/mitophagy in PMM2-CDG. Manipulating mitochondrial dysfunction and alterations in autophagy/mitophagy pathways could offer therapeutic benefits when combined with existing treatments for PMM2-CDG. MDPI 2023-08-04 /pmc/articles/PMC10454768/ /pubmed/37628636 http://dx.doi.org/10.3390/genes14081585 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ligezka, Anna N.
Budhraja, Rohit
Nishiyama, Yurika
Fiesel, Fabienne C.
Preston, Graeme
Edmondson, Andrew
Ranatunga, Wasantha
Van Hove, Johan L. K.
Watzlawik, Jens O.
Springer, Wolfdieter
Pandey, Akhilesh
Morava, Eva
Kozicz, Tamas
Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG
title Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG
title_full Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG
title_fullStr Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG
title_full_unstemmed Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG
title_short Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG
title_sort interplay of impaired cellular bioenergetics and autophagy in pmm2-cdg
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454768/
https://www.ncbi.nlm.nih.gov/pubmed/37628636
http://dx.doi.org/10.3390/genes14081585
work_keys_str_mv AT ligezkaannan interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT budhrajarohit interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT nishiyamayurika interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT fieselfabiennec interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT prestongraeme interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT edmondsonandrew interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT ranatungawasantha interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT vanhovejohanlk interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT watzlawikjenso interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT springerwolfdieter interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT pandeyakhilesh interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT moravaeva interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg
AT kozicztamas interplayofimpairedcellularbioenergeticsandautophagyinpmm2cdg