This article [Palmieri et al., 2005: (http://hmg.oxfordjournals.org/cgi/content/full/14/20/3079)(http://www.ncbi.nlm.nih.gov/pubmed/16155110?dopt=Abstract)] is really interesting, and the authors described a patient who had no functional activity of the ANT1 isoform of the adenosine/adenine nucleotide translocase protein, which transports ADP into mitochondria and ATP out of the mitochondrial matrix, and had mitochondrial DNA (mtDNA) deletions in the skeletal muscles (and probably also the heart). The ANT1 isoform is the predominant isoform expressed in cardiac and skeletal muscles, and the authors describe the way the person had exercise intolerance and very gradual deterioration in fitness but did not demonstrate decompensated heart failure (Palmieri et al., 2005). The ANT1 isoform is also expressed in the brain, the authors say, but the authors say that the expression of the other isoforms is thought to be significant enough to compensate for the loss of functional ANT1 in different cell types in the brain (Palmieri et al., 2005).
That research may help explain the capacity of creatine supplementation to treat people who have mitochondrial disorders, and the mechanisms by which creatine can sometimes be beneficial in those conditions are not well-understood (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=creatine+monohydrate+mitochondrial). Not all of those studies have shown benefits, however. But creatine has sometimes been shown to decrease or abolish paracrystalline inclusions and other types of structural abnormalities in skeletal muscle mitochondria (or in the myocytes, more broadly). Even though creatine is clearly not a magic bullet, in any way, in the treatment of mitochondrial disorders, in my opinion, I do think there could be some potential, at low dosages, for creatine to prevent the accumulation of mtDNA deletions by its capacity to increase ADP recycling, via the functional coupling of mitochondrial creatine kinase activity (which is in the intermembrane space and intercristae space, outside the mitochondrial matrix) [Dolder et al., 2003: (http://www.jbc.org/cgi/content/full/M208705200)(http://www.ncbi.nlm.nih.gov/pubmed/12621025)] (it's actually thought to form complexes with ANT proteins) to adenine nucleotide translocase activity [Barbour et al., 1984: (http://www.jbc.org/cgi/reprint/259/13/8246)(http://www.ncbi.nlm.nih.gov/pubmed/6330105?dopt=Abstract); (http://scholar.google.com/scholar?q=%22nucleotide+translocase%22+%22creatine+kinase%22&hl=en&lr=)]. Essentially, ANT exports ATP from the mitochondrial matrix, and the activity of mitochondrial creatine kinase ensures, in the presence of an adequate pool of creatine, that ADP is recycled (it's the kinetics of the coupling reactions and spatial proximity, I think, that allow this to occur and to limit the loss of ADP, by diffusion, from the intermembrane space to the cytosol) back into the mitochondrial matrix. That's an oversimplification, but it conveys the concept. The intramitochondrial ADP pool has repeatedly been shown to be maintained, in a creatine-sensitive manner, somewhat or even largely independently of the cytosolic ADP pool, and the effect of creatine can be especially significant during ischemia, etc. This occurs despite the fact that there is no meaningful physical barrier (nothing like the inner mitochondrial membrane) to the diffusion of ADP from the intermembrane space to the cytosol proper. I guess the diffusion can be restricted to some extent, by the outer mitochondrial membrane, but I think the effect of the membrane is not all that significant.
It's important to note, though, that I think the therapeutic dosage range of creatine is fairly small (maybe 1-3 grams/day), but that's just my opinion. I think it has the potential, at higher dosages (or, conceivably, at any dosage in someone with liver disease, for example) to interfere with the transport of other guanidino compounds, including urea cycle intermediates, but that's just my opinion. I've discussed those issues in past postings.
There's actually more research showing that some bisphosphonates can induce apoptosis by forming either xenobiotic-and nucleotide-containing polyphosphates or can inhibit mevalonate-pathway enzymes and increase the formation of endogenous dinucleotide triphosphates, such as inosine triphosphoadenosine (IpppA), and those dinucleotides or dinucleotide-mimetics can inhibit adenine nucleotide translocase activity and thereby contribute to the pro-apoptotic effects of some bisphosphonates in cultured cells, etc. [Monkkonen et al., 2006: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1616989)(http://www.ncbi.nlm.nih.gov/pubmed/16402039)]. This is not always "bad," providing one can effectively target the cells one wants to target. In any case, I have to say that that mechanism doesn't sound very good to me, for many reasons, but that's just my opinion. And a person would obviously want to weigh the risks vs. the benefits in all of these cases and discuss all of those issues with one's doctor before doing anything. There are some case studies included in this search result list that are disturbing to me, and I really shouldn't get into some of these obscure topics sometimes (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=bisphosphonate+mitochondrial+translocase). I end up just finding more and more things I'd almost rather not know about, but I'm probably too idealistic.
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