Health

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

Publikation aus Health

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. R., Sinner F., Dengjel J., van Leeuwen F., Kroemer G., Madeo F.

Cell Reports (Impact Factor: 7.21). 03/2015; 10(9):1557-1571, 3/2015

Abstract:

<abstracttext>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 atmitochondria has potentially far-reaching pathophysiological implications.</abstracttext>