Proteasome inhibition and the mitochondria

The proteasome is an essential agent in cellular protein turnover, recognizing and targeting polyubiquitinated proteins for degradation — a process that serves both a regenerative function (by turning proteins back into amino acids, the raw materials for proteins yet to be synthesized) and a regulatory one (a protein that has been degraded can no longer act within the cell).

Papa and Rockwell report that reversible proteasome inhibition has long-term effects on the mitochondria, causing diminished energy production and increased generation of reactive oxygen species (ROS) in neurons. This increase in oxidative stress, in turn, results in increased cell death via apoptosis:

Persistent mitochondrial dysfunction and oxidative stress hinder neuronal cell recovery from reversible proteasome inhibition

Oxidative stress, proteasome impairment and mitochondrial dysfunction are implicated as contributors to ageing and neurodegeneration. Using mouse neuronal cells, we showed previously that the reversible proteasome inhibitor, [N-benzyloxycarbonyl-Ile-Glu (O-t-bytul)-Ala-leucinal; (PSI)] induced excessive reactive oxygen species (ROS) that mediated mitochondrial damage and a caspase-independent cell death. Herein, we examined whether this insult persists in neuronal cells recovering from inhibitor removal over time. Recovery from proteasome inhibition showed a time and dose-dependent cell death that was accompanied by ROS overproduction, caspase activation and mitochondrial membrane permeabilization with the subcellular relocalizations of the proapoptotic proteins, Bax, cytochrome c and the apoptosis inducing factor (AIF). Caspase inhibition failed to promote survival indicating that cell death was caspase-independent. Treatments with the antioxidant N-acetyl-cysteine (NAC) were needed to promote survival in cell recovering from mild proteasome inhibition while overexpression of the antiapoptotic protein Bcl-xL together with NAC attenuated cell death during recovery from potent inhibition. Whereas inhibitor removal increased proteasome function, cells recovering from potent proteasome inhibition showed excessive levels of ubiquitinated proteins that required the presence of NAC for their removal. Collectively, these results suggest that the oxidative stress and mitochondrial inhibition induced by proteasome inhibition persists to influence neuronal cell survival when proteasome function is restored.

Here’s what caught my eye about this paper: Mitochondrial ROS production is widely considered to play a causative role in cellular aging. Mitochondria, in turn, accumulate damage over the lifespan, which causes an acceleration in ROS production — a nasty positive-feedback loop. Based on these findings, however, I wonder whether the decline in mitochondrial function could be driven not only from within (by oxidative damage to mitos causing further oxidation), but also from without: We know that proteasome efficiency also declines during aging; it would seem likely that this functional decline could further erode mitochondrial function.

One corollary of this hypothesis is that even if we were able to completely eliminate oxidative damage, we’d still suffer diminution in mitochondrial capacity as a result of proteasomal decline –unless, of course, this decline and its effect on mitochondria operate via a non-oxidative mechanism, in which case eliminating oxidative damage would kill two birds with one stone.


One comment

  1. “One corollary of this hypothesis is that even if we were able to completely eliminate oxidative damage, we’d still suffer diminution in mitochondrial capacity as a result of proteasomal decline”

    Well, yeah the mitochondria are dependent upon the nuclear genome for a wide variety of proteins. The small Mito-DNA produce only a limited number of proteins/enzymes. Hence decline in one produces decline in the other.

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