Some Structure-Activity Relationships Among Drugs That Produce Uncoupling in Mitochondria: Are the pKa's and Log P Values Really the Key Requirements?

This is an interesting article that goes into some of the structural features [Terada, 1990: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1567840&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2176586)] of drugs that uncouple the oxidation-reduction reactions of the respiratory chain enzymes (which are the enzyme complexes I, II, III, and IV) from the phosphorylation of ADP by F0F1-ATPase ("complex V") (this is what is meant by "uncoupling," although many authors use the term loosely and refer to other processes as being forms of "uncoupling," etc.). In my opinion, it's not just the presence of a strong electron-withdrawing group that makes these drugs' structures distinctive. I bet those drugs undergo redox cycling and generate reactive oxygen species. How could they not, in the inner mitochondrial membrane? A lot of those look like really reactive molecules. I think the equation they give, which estimates the potential for a drug to induce uncoupling, is not going to be uniformly valid, because some drugs are weak acids or weak bases and can't form these kinds of reactive metabolites that the authors discuss. Some of those drugs are like benzoquinones, basically. I wonder if excessive amounts of coenzyme Q10 can cause proton cycling across the inner mitochondrial membrane, apart from the effect of CoQ10 as a cofactor for the uncoupling proteins (and for respiratory chain enzymes, of course). Because "mild uncoupling," as discussed in many articles, reduces superoxide production in mitochondria and can be beneficial in other ways. The effects of these drugs in these articles are really at one extreme. They're extremely potent uncouplers. The requirement that the drug be relatively planar (to favor overlap of the pi orbitals, presumably, in part) to be an extreme uncoupler is probably more important than the pKa value per se, in my opinion. Here's another article that discusses some of the other types of drugs that can produce mitochondrial toxicity [Wallace and Starkov, 2000: (http://oxphos.com/staticfile/pubs/Mitochondrial%20targets%20of%20drug%20toxicity.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/10836141)]. In my opinion, a lot of the research on CoQ10 gives the false impression that it's beneficial in a wide variety of contexts in which energy metabolism has become dysfunctional. CoQ10 is vastly overrated, in my opinion, as a tool in treating mitochondrial dysfunction in people without mitochondrial disorders. Its reactivity compromises its usefulness, in my opinion, and there are plenty of situations in which increasing the activities of respiratory chain enzymes (such as through the administration of exogenous CoQ10) is, in my opinion, very undesirable and counterproductive. A lot of authors refer to all of these various cofactors or substrates (compounds that have been researched as potential treatments for disturbances in energy metabolism) as if they are equivalent or produce the same effects, and different approaches can have drastically different effects under different circumstances. This example is not even especially relevant to the problems that can occur, in my opinion, with the use of CoQ10, but, when a person or animal is healthy and experiences some injury that causes ischemia, there may be mild or no structural damage to the mitochondria at first. Days later, after the calcium influx and swelling of the mitochondria has caused structural damage, the effects of something like CoQ10, especially, could, in my opinion, become undesirable. To be useful as a neuroprotective, something should produce durable effects under a variety of conditions. If a compound's very structure can cause it to generate reactive oxygen species in a wild and unregulated way, under slightly-less-than-ideal and less-than-tidy, laboratory conditions, then the compound is not going to be especially useful, in my opinion.