2. NQO1 regulates the level of the co-activator, PGC-1a,within the cell by controlling degradation rate via the 20S proteasome.
PGC-1a is my “favorite co-activator” because it is so important in mitochondrial biogenesis. I always thought that exercise activated PGC-1a gene via the “exercise kinase” called AMPK. (See he blog enry PGC-1-alpha and exercise). This is why I was shocked to find out that NQO1 actually regulates PGC-1a, not by the increase in expression of the NQO1 gene, but the the rate that PGC-1a is degraded. Expression of NQ01 keeps PGC-1a from being degraded. What I found out is that the level of PGC-1a protein in a cell is primarily determined by its degradation rate, not its synthesis rate.
Like many regulatory factors, PGC-1a has an extremely short half life. All of these extremely short-lived proteins are regulated by degradation rates, not synthesis rates. In the past, it was thought that PGC-1a degradation was only regulated by the ubiquitin-proteasome system (UPS). The UPS method involves a “protein tagger” that goes around putting a ubiquitin “tag” on the protein to be degraded.
Introduce: the 20S proteasome
However, recently a new process of proteasomal degradation has been discovered that does NOT involve any ubiquitination. Specifically, this proteasome does NOT require ubiquitination of the protein and this proteasome system is called the “20S proteasome catalytic particle” (aka 20S PC). Unlike the ubiquitin-dependent, 26S proteasome system (UPS), the 20S proteasome does not require protein unfolding to degrade the protein. (i.e. it can degrade proteins even without unfolding them). Moreover, the 20S proteasome can handle oxidized proteins much better than the UPS 26S proteasome. As a consequence, the 20S proteasome is the “oxidized protein degrader in stressed cells”. For instance, it takes 4 times as much hydrogen peroxide to inhibit the 20S proteasome as it does to inhibit the 26S proteasome of the UPS.
Introducing: intrinsically disordered proteins (IDPs)
Not all proteins are degraded by the 20S proteasome, however. The main type of proteins degraded by the 20S PC system are called “intrinsically disordered proteins” (or IDPs). Interestingly, the 20S proteasome system seems to be regulated by oxidative stress, via the glutathionylation of cysteine residues in the alph-rings of the 20S proteasome.
In conclusion, PGC-1a is a “intrinsically disordered protein” (IDP) that is regulated by its degradation rate. When PGC-1a is damaged by oxidation or when the cell is under oxidative stress (like with aging), the 20S proteasome controls its degradation rate and thus the levels of PGC-1a within the cell. Other IDPs besides PGC-1a include p53, c-fos, C/EBPa, p63, p33, p73a, and ornithine decarboxylase (ODC).
Interestingly, the 20S PC system has a “gate keeper” that inhibits the IDPs from being degraded. Guess who the “gatekeeper” is for 20S PC? Yes, it is NQO1. That is how NQO1 expression keeps PGC-1a around.
There is strong evidence now that the levels of PGC-1a in cells is regulated primarily by the degradation rate of PGC-1a, and only secondarily by the gene expression of the PGC-1a gene. There are two degradation pathways for PGC-1a. The two pathways are the Ubiquitin Proteasome system (UPS) and the ubiquitin-independent proteasome system called 20S PC..
Under conditions of no oxidative stress, the UPS system may regulate PGC-1a levels within the cell. However when the cell is under cellular stress and the PGC-1a protein is damaged by ROS-induced oxidation, the 20S proteasome controls the degradation rate of PGC-1a. NQO1 is the “gate-keeper” for this 20S PC system that prevents PGC-1a from being degraded during periods of cellular oxidative stress. Thus with aging, the 20S PC system is more important than the26S proteasome (i.e. the UPS) and thus the 20S proteasome degrades PGC-1a in the cell, unless NQO1 protects it from degradation. Thus it appears that under conditions of oxidative stress, such as with aging, NQO1 may be a major factor that controls the concentration of PGC-1a in the cell.