Proteasome modulates mitochondrial function during cellular senescence

Abstract

Proteasome plays fundamental roles in the removal of oxidized proteins and in the normal degradation of short-lived proteins. Previously we have provided evidences that the impairment in proteasome observed during the replicative senescence of human fibroblasts has significant effects on MAPK signaling, proliferation, life span, senescent phenotype and protein oxidative status. These studies have demonstrated that proteasome inhibition and replicative senescence caused accumulation of intracellular protein carbonyl content. In this study, we have investigated the mechanisms by which proteasome dysfunction modulates protein oxidation during cellular senescence. The results indicate that proteasome inhibition during replicative senescence have significant effects on the intra and extracellular ROS production in vitro. The data also show that ROS impaired the proteasome function, which is partially reversible by antioxidants. Increases in ROS after proteasome inhibition correlated with a significant negative effect on the activity of most mitochondrial electron transporters. We propose that failures in proteasome during cellular senescence lead to mitochondrial dysfunction, ROS production and oxidative stress. Furthermore, it is likely that changes in proteasome dynamics could generate a pro-oxidative condition at the immediate extracellular microenvironment that could cause tissue injury during aging, in vivo.

H2O2Accumulation Mediates Differentiation Capacity Alteration, But Not Proliferative Decline, in Senescent Human Fetal Mesenchymal Stem Cells

“…Accumulation of ROS is a common occurrence in senescent cells; studies have shown that induction of ROS in senescent cells is involved in inhibiting proliferation (14,41). We have also found intracellular accumulation of H 2 O 2 in senescent PDMCs, but the accumulation was not involved in inhibiting proliferation.…”

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

“…In C. elegans, fully functional 26S proteasome activity is required for normal stress resistance and lifespan (Ghazi et al 2007). Its inhibition induces mitochondrial dysfunction, ROS overproduction and oxidative stress (Torres and Perez 2008). It is therefore interesting that we found no evidence for positive selection of either 20S or 26S proteasome activity during the evolution of longevity in vertebrate endotherms.…”

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

“…Proteasome partial inhibition promotes a sub-lethal accumulation of ubiquitinated proteins that cannot be degraded, inducing cellular senescence instead of apoptosis (Cheng et al 2011). It has been reported (Torres and Perez 2008) that proteasome inhibitors induce ROS and mitochondrial dysfunction, generating an important effect on protein ubiquitination and further degradation as discussed before. However, depending on the proteasome inhibitor and the concentrations used, it might be possible that PIIPS cells would still be able to buffer redox state and maintain a Bhealthy^glutathione-redox balance.…”