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

doi:10.1016/j.celrep.2015.02.009

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

Cell Rep. 2015 Mar 10;10(9):1557-1571. doi: 10.1016/j.celrep.2015.02.009. Epub 2015 Mar 5.

Authors

Ralf J Braun¹, Cornelia Sommer², Christine Leibiger³, Romina J G Gentier⁴, Verónica I Dumit⁵, Katrin Paduch³, Tobias Eisenberg⁶, Lukas Habernig⁶, Gert Trausinger⁷, Christoph Magnes⁷, Thomas Pieber⁸, Frank Sinner⁸, Jörn Dengjel⁵, Fred W van Leeuwen⁴, Guido Kroemer⁹, Frank Madeo¹⁰

Affiliations

¹ Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany. Electronic address: ralf.braun@uni-bayreuth.de.
² Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
³ Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
⁴ Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands.
⁵ 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.
⁶ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
⁷ HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria.
⁸ HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria; Division of Endocrinology and Metabolism, Medical University of Graz, 8036 Graz, Austria.
⁹ Apoptosis, Cancer and Immunity Laboratory, Team 11, Equipe labellisée Ligue contre le Cancer, INSERM Cordeliers Research Cancer, 75006 Paris, France; Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75005 Paris, France.
¹⁰ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria. Electronic address: frank.madeo@uni-graz.at.

Abstract

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.

Abstract

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