11 replies to this topic

[niner]

A Russian group recently proposed (Christyakov et al.) a new mechanism for the biological effects of C60 reported by Baati. They think that the C60 cage is being protonated, in fact poly-protonated, and that the positive charge dispersed widely over the cage causes it to be attracted to the mitochondrial membrane, and to reduce the membrane potential. They say that the reduction of the membrane potential causes a mild uncoupling of respiration from phosphorylation, and results in a dramatically reduced production of superoxide.

I have some questions about this. An uncoupler should result in a reduction in ATP generation, along with an increase in thermogenesis, which doesn't seem to be what we observe. Many people notice an enhanced endurance that seems to me like it would be more consistent with an increase, rather than a decrease in ATP production.

They used a Density Functional Theory structure optimization which lead them to propose a rather curious endohedral structure for the cation- They find that up to a half dozen protons find their way INSIDE the C60 cage. A different group has modeled the protonated fullerene with a more conventional exo- structure, and obtained good agreement with experimental proton affinities. While I think that the Christyakov structure is probably a computational artifact, that doesn't mean their idea of it seeking out the mitochondrial membrane, in the manner of a Skulachev ion is wrong.

The concept of mild mitochondrial uncouplers, however, seems to be unsettled.

Comments?

[YOLF]

Maybe off topic, but what about attaching SkQ1 to C60? Would that achieve better results for the SkQ1 as well as the C60 or would it be redundant? I like the theory though. As I see it, ROS takes energy to clean up, so it's a matter of efficiency. If the amount of energy expended on cleaning up ROS increases more relative to the amount of energy being generated, then it's a net gain if you can just run cleaner and use less fuel. The superoxide that escapes the mitos is probably decreasing the number of ATP molecules that can be used or interfere with some other complimentary catabolism if the chemistry involved would indicate that this is not the case.

[hav]

The Christyakov paper seems to be based on concepts I previously came across in relation to optimizing fuel cells...
http://www.springer....2204-p173838515

Kind of interesting that they postulate up to 6 protons getting attracted and trapped inside the c60 cage to give it a net positive charge. Not sure I understand their theory of where the protons are normally coming from... that they normally exist inside the mitochondria and cause it to normally suck up any ROS that pass by? If that's the case, wouldn't those loose protons normally hanging out inside the mitochondria membranes deactivate ROS without the help of c60?

Too bad their simulation didn't consider the possible effect of oxygen molecules in proximity of c60. I have the impression that's more likely than water in proximity considering that c60 is more lipophilic than hydrophilic.

Howard

[niner]

Kind of interesting that they postulate up to 6 protons getting attracted and trapped inside the c60 cage to give it a net positive charge. Not sure I understand their theory of where the protons are normally coming from... that they normally exist inside the mitochondria and cause it to normally suck up any ROS that pass by? If that's the case, wouldn't those loose protons normally hanging out inside the mitochondria membranes deactivate ROS without the help of c60?

Too bad their simulation didn't consider the possible effect of oxygen molecules in proximity of c60. I have the impression that's more likely than water in proximity considering that c60 is more lipophilic than hydrophilic.

I think they really glossed over where the naked protons would come from. Normally, any protons would be pretty well attached to a water molecule, yielding an H3O+ ion. They seem to think such protons would occasionally jump off the water and bore into the interior of the c60. I think that's pretty unlikely, and that any transfer of a proton from the hydronium ion would involve a transition state where it was partially attached to two molecules; the one it was on and the one it's going to. In their model, they started with the proton already significantly removed from water and relatively close to the c60, which I think is an artificial situation.

Even if there were loose protons hanging around the mitochondria, they wouldn't deactivate ROS because the resulting molecule, if any, would still not have a closed shell configuration, since the proton wouldn't bring another electron along with it.

I suppose that oxygen molecules would be somewhat more likely to be found in a hydrophobic environment, but the density of water in the cell is so much higher than O2 (~1kg water/liter vs a few mg/liter for O2) that the oxygen molecules would be drastically outnumbered by water molecules.

[JohnD60]

I would not know where to start to do testing of electron transport chain uncoupling, but apparently such procedures exist based upon my quick review of the literature. I do not find a computer simulation persuasive. I will look forward to the cell culture testing results. And I don't think it is actually proven that electron transport chain uncoupling results in less free radical damage, I believe that is just speculation.

[niner]

I would not know where to start to do testing of electron transport chain uncoupling, but apparently such procedures exist based upon my quick review of the literature. I do not find a computer simulation persuasive. I will look forward to the cell culture testing results. And I don't think it is actually proven that electron transport chain uncoupling results in less free radical damage, I believe that is just speculation.

It's more than just speculation, in that there are experimental conditions under which it's observed. However, it doesn't sound like those conditions are exactly relevant to mitochondria in the real world. I agree about the lab work. We need some biochemists with mitochondrial expertise to run a few experiments to see what c60-oo is doing in the mitochondrion. I have a feeling that when the dust settles, mild uncoupling probably isn't going to remain standing.

Biochem Soc Trans. 2011 Oct;39(5):1305-9. doi: 10.1042/BST0391305.
Mitochondrial ('mild') uncoupling and ROS production: physiologically relevant or not?
Shabalina IG, Nedergaard J.

The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. irina.shabalina@wgi.su.se

During the last decade, the possibility that 'mild' uncoupling could be protective against oxidative damage by diminishing ROS (reactive oxygen species) production has attracted much interest. In the present paper, we briefly examine the evidence for this possibility. It is only ROS production from succinate under reverse electron-flow conditions that is sensitive to membrane potential fluctuations, and so only this type of ROS production could be affected; however, the conditions under which succinate-supported ROS production is observed include succinate concentrations that are supraphysiological. Any decrease in membrane potential, even 'mild uncoupling', must necessarily lead to large increases in respiration, i.e. it must be markedly thermogenic. Mitochondria within cells are normally ATP-producing and thus already have a diminished membrane potential, and treatment of cells, organs or animals with small amounts of artificial uncoupler does not seem to have beneficial effects that are explainable via reduced ROS production. Although it has been suggested that members of the uncoupling protein family (UCP1, UCP2 and UCP3) may mediate a mild uncoupling, present evidence does not unequivocally support such an effect, e.g. the absence of the truly uncoupling protein UCP1 is not associated with increased oxidative damage. Thus present evidence does not support mild uncoupling as a physiologically relevant alleviator of oxidative damage.

PMID: 21936806

[katzenjammer]

A serious athlete on Dat's board reports that his explosiveness has been way up but that conversely his aerobic capacity has not been favorably effected except that c60 has profoundly changed his recovery rate. This from an experienced athlete who knows his body and has tried to be aware of placebo effect. Maybe he's an outlier but it does possibly point to increased ATP.

[cuprous]

A serious athlete on Dat's board reports that his explosiveness has been way up but that conversely his aerobic capacity has not been favorably effected except that c60 has profoundly changed his recovery rate. This from an experienced athlete who knows his body and has tried to be aware of placebo effect. Maybe he's an outlier but it does possibly point to increased ATP.

Could you post a link please?

[katzenjammer]

A serious athlete on Dat's board reports that his explosiveness has been way up but that conversely his aerobic capacity has not been favorably effected except that c60 has profoundly changed his recovery rate. This from an experienced athlete who knows his body and has tried to be aware of placebo effect. Maybe he's an outlier but it does possibly point to increased ATP.

Could you post a link please?

Are you a member cuprous?

[Turnbuckle]

It seems more likely that C60 acts as an uncoupling protein (UCP2) inhibitor. This would explain greater ATP production and stem cell proliferation and differentiation, which seem to occur with C60 use and is normally inhibited by UCP2.

[cuprous]

A serious athlete on Dat's board reports that his explosiveness has been way up but that conversely his aerobic capacity has not been favorably effected except that c60 has profoundly changed his recovery rate. This from an experienced athlete who knows his body and has tried to be aware of placebo effect. Maybe he's an outlier but it does possibly point to increased ATP.

Could you post a link please?

Are you a member cuprous?

Didn't realize "Dat's board" was a members only affair. So - "no."

[katzenjammer]

A serious athlete on Dat's board reports that his explosiveness has been way up but that conversely his aerobic capacity has not been favorably effected except that c60 has profoundly changed his recovery rate. This from an experienced athlete who knows his body and has tried to be aware of placebo effect. Maybe he's an outlier but it does possibly point to increased ATP.

Could you post a link please?

Are you a member cuprous?

Didn't realize "Dat's board" was a members only affair. So - "no."

Didn't mean to sound mysterious

If your into training/peps, and all of stuff around that, there's no place better on earth to discuss with like-minded. If you're interested pm me.

~katz