Accumulation of basic amino acids at mitochondria dictates the cytotoxicity of aberrant ubiquitin

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 atmitochondria 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 mitochondriahaspotentially far-reaching pathophysiological implications.