title: Negative regulation of 26S proteasome stability via calpain-mediated cleavage of Rpn10 subunit upon mitochondrial dysfunction in neurons.
abstract: Proteasomal and mitochondrial dysfunctions are implicated in chronic neurodegenerative diseases. To investigate the impact of mitochondrial impairment on the proteasome, we treated rat cerebral cortical neurons with oligomycin, antimycin, or rotenone, which inhibit different elements of the electron transport chain. Firstly, we observed a reduction in ubiquitinated proteins and E1 activity. Secondly, we established that 26S proteasomes are disassembled with a decline in activity. Thirdly, we show, to our knowledge for the first time, that calpain activation triggers the selective processing of the 26S proteasome subunit Rpn10. Other proteasome subunits tested were not affected. Calpain also cleaved caspase 3 to an inactive fragment, thus preventing apoptosis that is an energy-dependent cell death pathway. In addition, calpain cleaved the microtubule-associated protein Tau, a major component of neurofibrillary tangles in Alzheimer disease and other tauopathies. Fourthly, we detected a rise in 20S proteasome levels and activity. Finally, we show that both acute (16 h) and long term (up to 7 days) mitochondrial impairment led to down-regulation of ubiquitinated-proteins, 26S proteasome disassembly, and a rise in 20S proteasomes. We postulate that upon mitochondrial dysfunction, ATP depletion and calpain activation contribute to the demise of protein turnover by the ubiquitin/proteasome pathway. The concomitant rise in 20S proteasomes, which seem to degrade proteins in an unregulated and energy-independent manner, in the short term may carry out the turnover of randomly unfolded oxidized proteins. However, if chronic, it could lead to neurodegeneration as regulated protein degradation by the ubiquitin/proteasome pathway is essential for neuronal survival.
authors.affiliation: Department of Biological Sciences, Hunter College and Graduate Center, City University of New York, New York, New York 10065, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Seth W
authors.initials: SW
authors.lastname: Perry
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueiredo-Pereira
mesh_terms: D000818:Animals; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004795:Enzyme Stability; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C489131:Mapt protein, rat; D057149:Ubiquitinated Proteins; D016875:tau Proteins; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease