Learn more: Oxidative Stress and Proteostasis

Endoplasmic reticulum stress as a progression factor for kidney injury
Curr. Opin. Pharmacol. 2010, view full abstract in PubMed

Dysfunction of endoplasmic reticulum (ER) maintaining protein homeostasis can result from various disturbances, including hypoxia or oxidative stress, which lead to an imbalance between protein-folding capacity and protein-folding load. This in turn leads to ER stress and induction of the unfolded protein response (UPR). The UPR initially serves as an adaptive response, but also induces apoptosis in cells under severe or prolonged ER stress. Accumulating evidence indicates that ER stress contributes to glomerular and tubular damages in kidney disease. These findings emphasize the importance of ER stress as a new progression factor and the interesting future possibility of renoprotective strategies targeting ER stress. These therapeutic approaches may act by breaking the vicious cycle of oxidative stress, hypoxia, and ER stress

Mitochondrial dysfunction, proteotoxicity, and aging: causes or effects, and the possible impact of NAD+-controlled protein glycation
Adv. Clin. Chem. 2010, view full abstract in PubMed

Aging is frequently characterized by the accumulation of altered proteins and dysfunctional mitochondria. This review discusses possible causes of these effects, their interdependence and the impact of energy metabolism on proteostasis, especially formation and elimination of altered proteins. It is suggested NAD+ to some degree regulates formation of aberrant proteins and generation of oxygen free-radicals and reactive oxygen species (ROS), because when NAD+ is limiting, glycolytic triose phosphates spontaneously decompose into methylglyoxal (MG), a highly deleterious glycating agent and ROS inducer. That NAD+ has stimulatory effects on stress protein expression and autophagy, while mitochondria regenerate NAD+ from NADH, further integrates energy metabolism into proteostasis. It is suggested that, as altered proteins can deleteriously interact with mitochondria, changes in synthesis, or elimination, of cytosolic error-proteins will affect mitochondrial activity. It is also suggested that functional mitochondria are essentially antiaging agents, while their dysfunction or inactivity accelerate ROS formation and aging. These proposals may also help explain the oxygen paradox that while ROS may be causal to aging, increased mitochondrial activity (i.e., oxygen utilization) suppresses aging and much associated pathology. Increased synthesis of glutathione, humanin, and mitochondrial chaperone proteins are other additional consequences of increased mitogenesis and which would help ensure proteostasis.

Proteotoxic stress increases nuclear localization of ataxin-3
Hum. Mol. Genet. 2010, view full abstract in PubMed

Spinocerebellar ataxia type 3 (SCA3)/Machado Joseph disease results from expansion of the polyglutamine domain in ataxin-3 (Atx3). Atx3 is a transcriptional co-repressor, as well as a deubiquitinating enzyme that appears to function in cellular pathways involved in protein homeostasis. In this study, we show that interactions of Atx3 with valosin-containing protein and hHR23B are dynamic and modulated by proteotoxic stresses. Heat shock, a general proteotoxic stress, also induced wild-type and pathogenic Atx3 to accumulate in the nucleus. Mapping studies showed that two regions of Atx3, the Josephin domain and the C-terminus, regulated heat shock-induced nuclear localization. Heat shock-induced nuclear localization of Atx3 was not affected by a casein kinase-2 inhibitor or by mutating a predicted nuclear localization signal. However, serine-111 of Atx3 was required for nuclear localization of the Josephin domain and regulated nuclear localization of full-length Atx3. Atx3 null cells were more sensitive to toxic effects of heat shock suggesting that Atx3 had a protective function in the cellular response to heat shock. Importantly, we found that oxidative stress also induced nuclear localization of Atx3; both wild-type and pathogenic Atx3 accumulated in the nucleus of SCA3 patient fibroblasts following oxidative stress. Heat shock and oxidative stress are the first processes identified that increase nuclear localization of Atx3. Observations in this study provide new and important insights for understanding SCA3 pathology as the nucleus is likely a key site for early pathogenesis.

The role of protein quality control in mitochondrial protein homeostasis under oxidative stress
Proteomics. 2010, view full abstract in PubMed

Mitochondria contribute significantly to the cellular production of ROS. The deleterious effects of increased ROS levels have been implicated in a wide variety of pathological reactions. Apart from a direct detoxification of ROS molecules, protein quality control mechanisms are thought to protect protein functions in the presence of elevated ROS levels. The reactivities of molecular chaperones and proteases remove damaged polypeptides, maintaining enzyme activities, thereby contributing to cellular survival both under normal and stress conditions. We characterized the impact of oxidative stress on mitochondrial protein homeostasis by performing a proteomic analysis of isolated yeast mitochondria, determining the changes in protein abundance after ROS treatments. We identified a set of mitochondrial proteins as substrates of ROS-dependent proteolysis. Enzymes containing oxidation-sensitive prosthetic groups like iron/sulfur clusters represented major targets of stress-dependent degradation. We found that several proteins involved in ROS detoxification were also affected. We identified the ATP-dependent protease Pim1/LON as a major factor in the degradation of ROS-modified soluble polypeptides localized in the matrix compartment. As Pim1/LON expression was induced significantly under ROS treatment, we propose that this protease system performs a crucial protective function under oxidative stress conditions.