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

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cam.issuedOnline2021-10-06
dc.contributor.authorJennings, Matthew J
dc.contributor.authorHathazi, Denisa
dc.contributor.authorNguyen, Chi DL
dc.contributor.authorMunro, Benjamin
dc.contributor.authorMünchberg, Ute
dc.contributor.authorAhrends, Robert
dc.contributor.authorSchenck, Annette
dc.contributor.authorEidhof, Ilse
dc.contributor.authorFreier, Erik
dc.contributor.authorSynofzik, Matthis
dc.contributor.authorHorvath, Rita
dc.contributor.authorRoos, Andreas
dc.contributor.orcidMunro, Benjamin [0000-0003-4506-7092]
dc.contributor.orcidHorvath, Rita [0000-0002-9841-170X]
dc.date.accessioned2021-10-20T05:20:03Z
dc.date.available2021-10-20T05:20:03Z
dc.date.issued2021
dc.date.submitted2021-05-15
dc.date.updated2021-10-20T05:20:03Z
dc.description.abstractRecessive 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.
dc.identifier.doi10.17863/CAM.77110
dc.identifier.eissn2296-634X
dc.identifier.issn2296-634X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/329661
dc.languageen
dc.language.isoeng
dc.publisherFrontiers Media SA
dc.publisher.urlhttp://dx.doi.org/10.3389/fcell.2021.710247
dc.subjectDNAJC3
dc.subjectcholesterol-stress
dc.subjectmitochondria
dc.subjectproteomics
dc.subjectunfolded protein response (UPR)
dc.titleIntracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3.
dc.typeArticle
dcterms.dateAccepted2021-09-02
prism.publicationNameFront Cell Dev Biol
prism.volume9
pubs.funder-project-idMedical Research Council (MR/N025431/2)
pubs.funder-project-idMRC (MR/V009346/1)
pubs.funder-project-idWellcome Trust (109915_A_15_Z)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3389/fcell.2021.710247

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