Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease

Grune, Tilman; Jung, Tobias; Merker, Katrin; Davies, Kelvin J.A.

doi:10.1016/j.biocel.2004.04.020

Cited by 583 publications

(455 citation statements)

References 105 publications

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“…Such proteins tend to build hydrophobic and insoluble aggregates and are preliminary stages of the socalled lipofuscin (35)(36)(37), an indegradable and nonexocytosable material; in the literature sometimes also referred to as ''age pigment'' (38) or ''ceroid'' (39). If the proteolytic systems of the cell (40)(41)(42) fail to degrade oxidized proteins in time, the likelihood of cross-linking events increases and lipofuscin is formed. Since lipofuscin is able to inhibit the proteasomal system (43)(44)(45), thus reducing the degradation of other oxidized proteins and again increasing the amount of heavily oxidized and cross-linked indegradable proteins, this vicious cycle results Figure 1.…”

Section: Protein Oxidation In Mammalian Cellsmentioning

confidence: 99%

The proteasome and its role in the degradation of oxidized proteins

2008

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SummaryThe generation of free radicals and the resulting oxidative modification of cell structures are omnipresent in mammalian cells. This includes the permanent oxidation of proteins leading to the disruption of the protein structure and an impaired functionality. In consequence, these oxidized proteins have to be removed in order to prevent serious metabolic disturbances. The most important cellular proteolytic system responsible for the removal of oxidized proteins is the proteasomal system. For normal functioning, the proteasomal system needs the coordinated interaction of numerous components. This review describes the fundamental functions of the 20S ''core'' proteasome, its regulators, and the roles of the proteasomal system beyond the removal of oxidized proteins in mammalian cells. IUBMBIUBMB Life, 60(11): 743-752, 2008

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Section: Protein Oxidation In Mammalian Cellsmentioning

confidence: 99%

The proteasome and its role in the degradation of oxidized proteins

2008

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“…Upon c-interferon stimulation, these catalytic subunits can be replaced by inducible subunits ib1, ib2 and ib5 to form the so-called immunoproteasome which exhibits higher chymotrypsin-like and trypsin-like activities and lower peptidylglutamyl peptide hydrolase activity [24,25]. Oxidized proteins represent good substrates for the 20S proteasome unless they become heavily oxidized and cross-linked [26]. In such a situation, not only these highly damaged proteins become resistant to proteolysis by the proteasome but they can also act as inhibitors as clearly demonstrated for proteins crosslinked after modification by the lipid peroxidation product 4-hydroxy-2-nonenal [27,28].…”

Section: Reversible and Irreversible Protein Oxidative Damagementioning

confidence: 99%

Oxidized protein degradation and repair in ageing and oxidative stress

2006

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Cellular ageing is characterized by the accumulation of oxidatively modified proteins which may be due to increased protein damage and/or decreased elimination of oxidized protein.Since the proteasome is in charge of protein turnover and removal of oxidized protein, its fate during ageing and upon oxidative stress has received special attention, and evidence has been provided for an age-related impairment of proteasome function. However, proteins when oxidized at the level of sulfur-containing amino acids can also be repaired. Therefore, the fate of the methionine sulfoxide reductase system during ageing has also been addressed as well as its role in protection against oxidative stress.

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“…Although it has been known for some time that mildly damaged mitochondrial proteins are degraded by the proteasome, it hasn't been appreciated until recently that heavily damaged mitochondrial proteins inhibit the proteasome [66][67][68][69][70]. Thus, the very strong inhibition of many subunits of the ubiquitin-proteasome system is likely a consequence of misfolded and damaged mitochondrial proteins specified by the mtDNA deletions.…”

Section: Deletions Inhibit the Ubiquitin And Proteasome Systemmentioning

confidence: 99%

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

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Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease

Cited by 583 publications

References 105 publications

The proteasome and its role in the degradation of oxidized proteins

The proteasome and its role in the degradation of oxidized proteins

Oxidized protein degradation and repair in ageing and oxidative stress

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

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