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

doi:10.1016/j.celrep.2015.02.009

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

MHeNs - Neuroscience

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1557-1571
Journal	Cell Reports
Volume	10
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2015.02.009
Publication status	Published - 10 Mar 2015

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Braun, R. J., Sommer, C., Leibiger, C., Gentier, R. J. G., Dumit, V. I., Paduch, K., Eisenberg, T., Habernig, L., Trausinger, G., Magnes, C., Pieber, T., Sinner, F., Dengjel, J., van Leeuwen, F. W., Kroemer, G., & Madeo, F. (2015). Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin. Cell Reports, 10(9), 1557-1571. https://doi.org/10.1016/j.celrep.2015.02.009

@article{1506425e999d4bd7ab40f79e379d3503,

title = "Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin",

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.",

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

year = "2015",

month = mar,

day = "10",

doi = "10.1016/j.celrep.2015.02.009",

language = "English",

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Braun, RJ, Sommer, C, Leibiger, C, Gentier, RJG, Dumit, VI, Paduch, K, Eisenberg, T, Habernig, L, Trausinger, G, Magnes, C, Pieber, T, Sinner, F, Dengjel, J, van Leeuwen, FW, Kroemer, G & Madeo, F 2015, 'Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin', Cell Reports, vol. 10, no. 9, pp. 1557-1571. https://doi.org/10.1016/j.celrep.2015.02.009

TY - JOUR

T1 - Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin

AU - Braun, Ralf J.

AU - Sommer, Cornelia

AU - Leibiger, Christine

AU - Gentier, Romina J. G.

AU - Dumit, Veronica I.

AU - Paduch, Katrin

AU - Eisenberg, Tobias

AU - Habernig, Lukas

AU - Trausinger, Gert

AU - Magnes, Christoph

AU - Pieber, Thomas

AU - Sinner, Frank

AU - Dengjel, Joern

AU - van Leeuwen, Fred W.

AU - Kroemer, Guido

AU - Madeo, Frank

PY - 2015/3/10

Y1 - 2015/3/10

N2 - 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.

AB - 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.

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DO - 10.1016/j.celrep.2015.02.009

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