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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |