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

Ralf J. Braun*, Cornelia Sommer, Christine Leibiger, Romina J. G. Gentier, Veronica I. Dumit, Katrin Paduch, Tobias Eisenberg, Lukas Habernig, Gert Trausinger, Christoph Magnes, Thomas Pieber, Frank Sinner, Joern Dengjel, Fred W. van Leeuwen, Guido Kroemer, Frank Madeo

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)1557-1571
JournalCell Reports
Issue number9
Publication statusPublished - 10 Mar 2015

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