کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2040929 1073136 2015 15 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin
ترجمه فارسی عنوان
تجمع اسید آمینه پایه در میتوکندریا، سمیت سلولهای توکسین ابی را به وجود می آورد
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک علوم کشاورزی و بیولوژیک (عمومی)
چکیده انگلیسی


• UBB+1 co-exists with the UPS component VMS1 in neurofibrillary tangles
• UBB+1 accumulation impairs the UPS and mitochondria, triggering cell death
• UBB+1 causes accumulation of basic amino acids at mitochondria
• Vms1 reverts UBB+1-triggered basic amino acid accumulation and cell death

SummaryNeuronal 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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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 10, Issue 9, 10 March 2015, Pages 1557–1571
نویسندگان
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