Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin
Ralf J. Braun,
Cornelia Sommer,
Christine Leibiger,
Romina J.G. Gentier,
Verónica I. Dumit,
Katrin Paduch,
Tobias Eisenberg,
Lukas Habernig,
Gert Trausinger,
Christoph Magnes,
Thomas Pieber,
Frank Sinner,
Jörn Dengjel,
Fred W. van Leeuwen,
Guido Kroemer,
Frank Madeo
Affiliations
Ralf J. Braun
Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany
Cornelia Sommer
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
Christine Leibiger
Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany
Romina J.G. Gentier
Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
Verónica I. Dumit
FRIAS Freiburg Institute for Advanced Studies, Department of Dermatology, Medical Center, ZBSA Center for Biological Systems Analysis, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
Katrin Paduch
Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany
Tobias Eisenberg
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
Lukas Habernig
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
Gert Trausinger
HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria
Christoph Magnes
HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria
Thomas Pieber
HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria
Frank Sinner
HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria
Jörn Dengjel
FRIAS Freiburg Institute for Advanced Studies, Department of Dermatology, Medical Center, ZBSA Center for Biological Systems Analysis, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
Fred W. van Leeuwen
Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
Guido Kroemer
Apoptosis, Cancer and Immunity Laboratory, Team 11, Equipe labellisée Ligue contre le Cancer, INSERM Cordeliers Research Cancer, 75006 Paris, France
Frank Madeo
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
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.
