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 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.710247

DOI=10.3389/fcell.2021.710247

ISSN=2296-634X

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.