Cargando…

Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3

Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of s...

Descripción completa

Detalles Bibliográficos
Autores principales: Jennings, Matthew J., Hathazi, Denisa, Nguyen, Chi D. L., Munro, Benjamin, Münchberg, Ute, Ahrends, Robert, Schenck, Annette, Eidhof, Ilse, Freier, Erik, Synofzik, Matthis, Horvath, Rita, Roos, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526738/
https://www.ncbi.nlm.nih.gov/pubmed/34692675
http://dx.doi.org/10.3389/fcell.2021.710247
_version_ 1784585925886476288
author Jennings, Matthew J.
Hathazi, Denisa
Nguyen, Chi D. L.
Munro, Benjamin
Münchberg, Ute
Ahrends, Robert
Schenck, Annette
Eidhof, Ilse
Freier, Erik
Synofzik, Matthis
Horvath, Rita
Roos, Andreas
author_facet Jennings, Matthew J.
Hathazi, Denisa
Nguyen, Chi D. L.
Munro, Benjamin
Münchberg, Ute
Ahrends, Robert
Schenck, Annette
Eidhof, Ilse
Freier, Erik
Synofzik, Matthis
Horvath, Rita
Roos, Andreas
author_sort Jennings, Matthew J.
collection PubMed
description Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.
format Online
Article
Text
id pubmed-8526738
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-85267382021-10-21 Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3 Jennings, Matthew J. Hathazi, Denisa Nguyen, Chi D. L. Munro, Benjamin Münchberg, Ute Ahrends, Robert Schenck, Annette Eidhof, Ilse Freier, Erik Synofzik, Matthis Horvath, Rita Roos, Andreas Front Cell Dev Biol Cell and Developmental Biology Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation. Frontiers Media S.A. 2021-10-06 /pmc/articles/PMC8526738/ /pubmed/34692675 http://dx.doi.org/10.3389/fcell.2021.710247 Text en Copyright © 2021 Jennings, Hathazi, Nguyen, Munro, Münchberg, Ahrends, Schenck, Eidhof, Freier, Synofzik, Horvath and Roos. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Jennings, Matthew J.
Hathazi, Denisa
Nguyen, Chi D. L.
Munro, Benjamin
Münchberg, Ute
Ahrends, Robert
Schenck, Annette
Eidhof, Ilse
Freier, Erik
Synofzik, Matthis
Horvath, Rita
Roos, Andreas
Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
title Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
title_full Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
title_fullStr Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
title_full_unstemmed Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
title_short Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
title_sort intracellular lipid accumulation and mitochondrial dysfunction accompanies endoplasmic reticulum stress caused by loss of the co-chaperone dnajc3
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526738/
https://www.ncbi.nlm.nih.gov/pubmed/34692675
http://dx.doi.org/10.3389/fcell.2021.710247
work_keys_str_mv AT jenningsmatthewj intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT hathazidenisa intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT nguyenchidl intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT munrobenjamin intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT munchbergute intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT ahrendsrobert intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT schenckannette intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT eidhofilse intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT freiererik intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT synofzikmatthis intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT horvathrita intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3
AT roosandreas intracellularlipidaccumulationandmitochondrialdysfunctionaccompaniesendoplasmicreticulumstresscausedbylossofthecochaperonednajc3