Recently a few readers have been curious about the mitochondriogenesis aspects of PQQ. For instance, if pyrroloquinoline quinone leads to mitochondrial biogenesis through the activation of cell signaling molecules such as AMPK. It has been purposed that when AMPK is activated it leads to the up-regulation of Nampt… leading to an increase in NAD+… which in turn can potentially activate the sirtuins. The activation of sirtuins would then lead to the up-regulation of PGC1-alpha and perhaps lead to an increase in natural mitochondrial biogenesis.
The theory is a good one, although speculative, as there are no direct studies related specifically to PQQ, sirtuins, and Nampt. In reality, the process depends upon a number of factors, such as the previous history (e.g., whether exercising, dieting, or consuming a high carbohydrate or high-fat diet) and experimental models and environments. For a good answer to the question, one must also consider dose. The dose is always an important consideration in that overriding cell-signaling controls that were placed there for a purpose may not be that the best strategy (in many applications).
With respect to genes in the sirtuin family, most are associated with the repair of DNA and help to regulate genes that undergo altered expression with aging. Dieting (food restriction) can affect (activate) Sirtuin regulatory factors (cf. Biochem Pharmacol. 2002 63:2075-80). Moreover, regulatory factors such as CREB can activate sirtuins, in particular SIRT1. In contrast, carbohydrate response-element-binding protein (ChREBP), which can be influenced by carbohydrate intake, can repress the expression of SIRT1 (cf. EMBO Rep. 2011 10.1038/embor.2011.151 [Epub ahead of print as of 7/11]). Moreover, there are many other contrasting control-related options that have been described (cf. Marcella F. & Vittorio S. Comparing and Contrasting the Roles of AMPK and SIRT1 in Metabolic Tissues. Cell Cycle. 2008 7:3669–3679).
Consequently, with regard to PQQ, if the mechanism is similar to resveratrol, as recently described by Schirmer et al. (Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4, PGC1-alpha and NAMPT gene expression profiles in wild-type adult zebrafish liver; Mol Biol Rep. 2011 [Epub ahead of print] as of 7/11), and it would be necessary to assess this process with the addition of a number of other variables. For example, the data by Schimmer and associates suggest in their animal model (zebrafish), resveratrol did not change the mRNA levels of SIRT1 and PGC1-alpha and decreased the expression levels of the SIRT3, SIRT4, and Nampt genes, which is somewhat different than the possible chain of events we’ve purposed above.
To reiterate, the reasons for all the qualifications are their importance to interpreting effectors/modulators of cell signaling and related pathways. Consider that altering the NAD+/H ratio (e.g., because of a change in Nampt expression) can also alter the so-called energy charge of the cell (AMP/ADP/ATP ratios). An alteration in cell charge activates dozens of metabolic-related pathways (cf. BioEssays 23:1112-1119). Some of the branch points and pathways, when viewed as a linear sequence in contrast to something more complex may fit a hypothesis or may also appear to be counter-intuitive without more information.
Can mitochondria generated during mitochondriogenesis create free radicals?
The shortest answer is no. Consider a given mass of tissue. If for that tissue, we ask what is the most rate-limiting – the number of mitochondria or substrate and oxygen utilization? The best answer is usually substrate and oxygen. For typical activities, we have plenty of mitochondria and with normal rates of substrate utilization and hydrogen transfer, oxygen is efficiently converted to water. However, if substrates are: 1) limiting (i.e. from carbohydrates, lipids, or proteins/amino acids) as might be the case at the end of a long intense exercise, 2) or areas of tissue damage, wherein substrates might be used inappropriately used, 3) or aging, wherein the metabolic machinery encased in mitochondria is decreased – there is less potential for oxygen to be effectively converted to water. ROS (reactive oxidant species) may be generated to make the situation worst. Optimizing mitochondrial amount does not necessarily generate more ROS (except in situations where oxygen flux through the metabolic pathways in mitochondria is very rapid and/or is not efficiently utilized. This may happen during the course of running a marathon or sprinting, where relative to oxygen, the metabolic substrates used as fuel sources are limited. It can also happen when electron transport inhibitors uncouple electron transfer to oxygen. However, regarding each of these examples, a case may be made that recovery is better and faster when substrate utilization and oxygen become more in synch and when all of the mitochondrial machinery is functional and optimized. In areas of tissue damage, having more or optimizing mitochondrial function is consistently reported to lessen tissue damage due to ROS. There are now dozens of papers that support the notion that retarding aging is a direct function of optimizing mitochondrial function.
Regarding your other comments, we prefer not to think of PQQ as a vitamin. The claim was made, because of the misinterpretation of the original data used in support of that notion. Rather, pyrroloquinoline quinone is best categorized as one of several compounds that act as cell signaling molecules. It is also not clear how “massive” a dose of 10-20 mg PQQ per day actually is. The assays used to date in various studies have measured only PQQ. It is known that in human milk, about 80-90% of the PQQ is in derivation form (products derived from PQQ reacting with amino acids). Some of these derivatives have effects similar to PQQ in studies in vitro.