Oxidized proteins: Mechanisms of removal and consequences of accumulation

Abstract

SummaryElevated levels of oxidized proteins are reported in diseased tissue from age-related pathologies such as atherosclerosis, neurodegenerative disorders, and cataract. Unlike the precise mechanisms that exist for the repair of nucleic acids, lipids, and carbohydrates, the primary pathway for the repair of oxidized proteins is complete catabolism to their constitutive amino acids. This process can be inefficient as is evidenced by their accumulation. It is generally considered that damaged proteins are degraded by the proteasome; however, this is only true for mildly oxidized proteins, because substrates must be unfolded to enter the narrow catalytic core. Rather, evidence suggests that moderately or heavily oxidized proteins are endocytosed and enter the endosomal/lysosomal system, indicating co-operation between the proteasomes and the lysosomes. Heavily modified substrates are incompletely degraded and accumulate within the lysosomal compartments resulting in the formation of lipofuscin-like, autofluorescent aggregates. Accumulation eventually results in impaired turnover of large organelles such as proteasomes and mitochondria, lysosomal destablization, leakage of proteases into the cytosol and apoptosis. In this review, we summarize reports published since our last assessments of the field of oxidized protein degradation including a role for modified proteins in the induction of apoptosis.

Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer’s-Like Neurodegeneration

“…Further, oxidation of proteins increases the susceptibility of a protein to degradation by the 20S proteasomes and, consequently, decreases levels of the proteins in general. However, in certain diseases, oxidation of proteasome components has been reported and defective proteasome consequently leads to accumulation of damaged proteins within the cells [6]. Deposits of aggregated, misfolded, and oxidized proteins accumulate normally over time in cells and tissues and are often present in increased amounts in a range of age-related disorders, such as neurodegenerative diseases.…”

“…Protein oxidation refers to the direct or indirect damage of a protein as a consequence of oxidative insult, often making the protein dysfunctional or nonfunctional [6]. This process inevitably affects protein structure and could lead to the alteration in the secondary and tertiary structure of proteins including dissociation of subunits, unfolding, exposure of hydrophobic residues, aggregation, and backbone fragmentation [7].…”

“…All amino acid residues are potential targets for oxidation by ROS, with methionine and cysteine residues being particularly sensitive. In the case of methionine, methionine sulfoxide (MeSOX) can be reduced by MeSOX reductases, whereas oxidation of sulfhydryl groups, often resulting in the formation of intraor intermolecular disulphides, is reduced back by disulfide reductases/isomerases [6]. These are the only known oxidative modifications of proteins that can be enzymatically repaired in mammalian systems.…”

Relationship Between Protein Oxidation Markers and Oxidative Stress Biomarkers

“…Deposits of aggregated, misfolded, and oxidized proteins accumulate normally over time in cells and tissues, especially in postmitotic cells of the brain and heart, and are often present in increased amounts in a range of age-related disorders, such as atherosclerosis, neurodegeneration, and cataractogenesis (Dunlop et al 2009;Dunlop Ra Fau -Rodgers et al 2002). Oxidatively modified proteins are usually considered degraded more or less exclusively by the proteasome system, although this would only apply to mildly oxidized proteins since substrates must be unfolded to enter the narrow catalytic chamber of the 20S core (Dunlop Ra Fau -Rodgers, Rodgers Kj Fau -Dean, & Dean 2002).…”

Influence of L-Nω-nitroarginine methyl ester and sodium nitroprusside in vitro on the oxidative modification of rat lysosome proteins

“…Одним из возможных механизмов сни-жения резервно-адаптационного потен-циала может оказаться ингибирование активности протеолитических ферментов лизосом, участвующих в утилизации окис-лительно-модифицированных молекул [11].…”