NQO1 reguliert PGC-1a

#1 von Fichtennadel , 19.02.2019 12:20

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).





http://www.anti-agingfirewalls.com/2015/...-interventions/




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.

Summary:

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.


Chris (edubily) hat sich bedankt!
Fichtennadel  
Fichtennadel
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RE: NQO1 reguliert PGC-1a

#2 von Fichtennadel , 11.03.2019 16:53

Ich poste das hier nur Auszugsweise, die ursprünglichen Abhandlungen auf "antiageing-firewalls" sind sehr umfangreich aber unendlcih lehrreich:

Die ganz "NAD-World"-Serie (4 Teile) von James Watson sind konzentriertes, aktuelles Wissen rund um NAD:
http://www.anti-agingfirewalls.com/2014/...he-nad-world-2/


Folgendens fand ich für Edubily interessant, denn Chris stellte ja auch schon einige Calorie-Restrictions- bzw. Fastenmimetik-Ansätze vor.
Hier geht es nochmal um NQO1. Beta-Lapachpon aus dem Pau d'Arco-Rindentee steigert nicht nur via NQO1-Enzymaktivitätserhöhung die NAD/NADH-RAtion sondern induziert
im murinen Versuch eine veränderte Genexpression der Tiere, die einer Kalorie-Restriktion ähnelt:


http://www.anti-agingfirewalls.com/2015/...life-extension/

2. NAD/NADH ratio regulates aging independently of NAD content

–The longevity gene, NQO1, regulates aging by altering the NAD/NADH ratio in cells. NQO1 does this by oxidizing NADH to NAD. Beta-lapachone increases NQO1 enzyme activity and quercetin increases Nrf2-mediated gene expression of NQO1.

Not only is the NAD content in the nucleus important for delaying/preventing aging, the redox ratio of NAD/NADH is also very important for delaying/preventing aging independently of the total NAD found in the cell. Many genetic studies in model organisms have searched for “longevity genes” that regulate lifespan. One of the curious findings from these studies is the gene that codes for the protein “NADH-quinone oxidoreductase 1″, or NQO1. NQO1 oxidizes NADH to NAD, thereby increasing the NAD/NADH ratio. Interestingly, Lee and colleagues from Korea recently showed that feeding animals beta-lapachone (aka Beta-L), an exogenous NQO1 co-substrate, prevented the age-dependent decline of motor and cognitive function in aged mice. Beta-lapchone is a compound originally obtained from the Lapcho tree and has been used for medical purposes for many years. Beta-L fed mice did not alter their food intake or locomotor activity, but did increase their energy expenditure as measured by VO2max and by heat generation. The Beta-L fed mice developed changes in gene expression that mimicked 30% caloric restricted diets. Another molecular effect of beta-Lapachone is that it induces apoptosis in breast and prostate cancer cells.




ß-Lapachon kann noc ganz viel mehr, ist in Part 4 der Seire nachzulesen. Vlt. ist das Edubily im Laufe der Zeit mal einen Artikel wert. Unser gemeinsamer spezieller Freund ist seit langem ein Proponent der Chinone insbs. auch des ß-Lapachons. Er wird durch neuere Studien dabei bestätiigt.


Chris (edubily), Wirbelwind und Mr. Xu haben sich bedankt!
Fichtennadel  
Fichtennadel
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Registriert am: 29.11.2018


RE: NQO1 reguliert PGC-1a

#3 von Fichtennadel , 13.03.2019 12:56

Haha, jetzt habe ich nur geschrieben "unser gemeinsamer spezieller Freund" ohne den Namen zu nennen. Das klingt doch leicht bekloppt. Wer es nicht erraten konnte: Raymond Peat.


Fichtennadel  
Fichtennadel
Beiträge: 11
Registriert am: 29.11.2018


   

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