Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin

Title data

Braun, Ralf J. ; Sommer, Cornelia ; Leibiger, Christine ; Gentier, Romina J.G. ; Dumit, Verónica I. ; Paduch, Katrin ; Eisenberg, Tobias ; Habernig, Lukas ; Trausinger, Gert ; Magnes, Christoph ; Pieber, Thomas ; Sinner, Frank ; Dengjel, Jörn ; van Leeuwen, Fred W. ; Kroemer, Guido ; Madeo, Frank:
Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin.
In: Cell Reports. Vol. 10 (2015) Issue 9 . - 1557 -1571.
ISSN 2211-1247
DOI der Verlagsversion: https://doi.org/10.1016/j.celrep.2015.02.009

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Abstract

Summary Neuronal accumulation of UBB+1, a frameshift variant of ubiquitin B, is a hallmark of Alzheimer’s disease (AD). How UBB+1 contributes to neuronal dysfunction remains elusive. Here, we show that in brain regions of {AD} patients with neurofibrillary tangles UBB+1 co-exists with VMS1, the mitochondrion-specific component of the ubiquitin-proteasome system (UPS). Expression of UBB+1 in yeast disturbs the UPS, leading to mitochondrial stress and apoptosis. Inhibiting {UPS} activity exacerbates while stimulating {UPS} by the transcription activator Rpn4 reduces UBB+1-triggered cytotoxicity. High levels of the Rpn4 target protein Cdc48 and its cofactor Vms1 are sufficient to relieve programmed cell death. We identified the UBB+1-induced enhancement of the basic amino acids arginine, ornithine, and lysine at mitochondria as a decisive toxic event, which can be reversed by Cdc48/Vms1-mediated proteolysis. The fact that AD-induced cellular dysfunctions can be avoided by {UPS} activity at mitochondria has potentially far-reaching pathophysiological implications.

Further data

Item Type:	Article in a journal
DDC Subjects:	500 Science > 570 Life sciences, biology
Institutions of the University:	Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology > Professor Cell Biology Faculties Faculties > Faculty of Biology, Chemistry and Earth Sciences Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology
Language:	English
Originates at UBT:	Yes
Date Deposited:	08 Feb 2017 10:44
Last Modified:	21 Sep 2023 12:20
URI:	https://epub.uni-bayreuth.de/id/eprint/3124

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