Dataset Information

Intracellular lipid accumulation and mitochondrial dysfunction accompanies ER-stress caused by loss of the co-chaperone DNAJC3

ABSTRACT: 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, a defect of APP. 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, Aβ accumulation and impairment of mitochondrial oxidative phosphorylation.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Neurodegenerative Disease,Type 2 Diabetes Mellitus

SUBMITTER: Denisa Hathazi

LAB HEAD: Dr. Andreas Roos

PROVIDER: PXD028168 | Pride | 2022-02-15

REPOSITORIES: Pride

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Publications

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

Jennings Matthew J MJ Hathazi Denisa D Nguyen Chi D L CDL Munro Benjamin B Münchberg Ute U Ahrends Robert R Schenck Annette A Eidhof Ilse I Freier Erik E Synofzik Matthis M Horvath Rita R Roos Andreas A

Frontiers in cell and developmental biology 20211006

Recessive mutations in <i>DNAJC3</i>, 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 funct ...[more]

PMID: 34692675

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Project description:SIL1 acts as a co-chaperone for the major ER-resident chaperone BiP and thus plays a role in many BiP-dependent cellular functions such as protein folding control and unfolded protein response. Whereas increase of BiP upon cellular stress conditions is a well-known phenomenon, elevation of SIL1 under stress conditions was thus far solely studied in yeast and different studies indicated an adverse effect of SIL1 increase. This is seemingly in contrast with the beneficial effect of SIL1 increase in surviving neurons in neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and Alzheimer disease. In the present study, we systematically addressed these controversial findings. Using cell biological, morphological and biochemical methods, we could demonstrate that that SIL1 is increased in various mammalian cells and neuronal tissues upon induction of cellular stress. Investigation of heterozygous SIL1/Sil1 mutant cells and tissues supported this finding. Moreover, SIL1 protein was found to be stabilized during ER stress. Increased SIL1 initiates ER stress in a concentration-dependent manner which is in accordance with the described adverse effect of increased SIL1. However, our results also suggest that protective levels are achieved by the secretion of excessive SIL1 and GRP170 (no longer perturbing ER homeostasis) and that moderately increased SIL1 also ameliorates cellular fitness under stress conditions. Results of our immunoprecipitation studies indicate that under cellular stress conditions SIL1 might act in a BiP-independent manner. Unbiased proteomic studies revealed that elevated SIL1 levels alter the expression of several proteins including crucial players in neurodegeneration, especially in Alzheimer disease. This finding is in accordance with our observation of increased SIL1-immunoreactivity in surviving neurons of Alzheimer disease autopsy cases and supports the assumption that SIL1 plays a protective role in neurodegenerative disorders.

Dataset Information

Intracellular lipid accumulation and mitochondrial dysfunction accompanies ER-stress caused by loss of the co-chaperone DNAJC3

Publications

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

Similar Datasets

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