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Loss of DNAJC3 impairs cholesterol metabolism and mitochondrial function

ABSTRACT: Recessive mutations in DNACJ3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. While minor ER morphology changes due to loss of DNAJC3 have been reported previously, the precise cellular pathophysiology is still elusive and not well understood. To further elucidate the cellular consequences of DNAJC3 loss we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways implying a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergics, 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 UPR, alterations of the ER-Golgi machinery, a defect of APP processing and concomitant Aβ accumulation. Moreover, we described here for the first-time alterations in mitochondrial morphology and oxidative phosphorylation as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects the lipid/cholesterol homeostasis, leading to UPR activation, Aβ accumulation and impaired protection against mitochondrial oxidative stress.

ORGANISM(S): Homo Sapiens

SUBMITTER: Chi Nguyen

PROVIDER: PXD027372 | panorama | Sat Jul 17 00:00:00 BST 2021

REPOSITORIES: PanoramaPublic

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Loss of DNAJC3 impairs cholesterol metabolism and mitochondrial function

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