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Mitochondrial Decouplers

mitochondria decouplers

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#1 pone11

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Posted 22 March 2015 - 11:24 PM


I found an interesting study that showed that "a small decrease in [mitochondrial] membrane potential (about 13%), [causes] a 2.2-fold increase in respiration rate and about 80% inhibition of H2O2 production."

http://www.sciencedi...014579397011599

 

Has anyone read enough of these mitochondrial uncoupling studies to know what is the effect on ATP production of a process change like the one above?   Does the 2.2 fold increase in respiration rate just go away as wasted potential energy?  Does the total ATP output:

 

* stay at the original level

* get lowered 13%, or get lowered >13%?

* go even higher than the original level because of the faster respiration rate

 

Assuming you could keep ATP even at a 13% lower output, the above seems to imply that if you could double the number of mitochondria, then lower mitochondrial membrane potential 13%, you would get 74% more energy output (87% + 87%) while lowering H2O2 creation by about 60% (you have to double the amount of H2O2 being created since there are now twice the number of energy factories/mitochondria).

 

While it seems outside the scope of anything we can control in vivo today, it still points out that there might be some deliberate engineering possible here that would fundamentally leave humans more energetic as they age, while simultaneously lowering their oxidative stress dramatically.   We have the chemicals to increase mitochondria and to decouple mitochondria.   What's lacking is a good way to establish dosing in vivo and monitor the effect so that you can adjust the throttles over time.

 



#2 Darryl

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Posted 23 March 2015 - 01:00 AM

Its certainly a fascinating avenue. Reducing mitochondrial ROS generation, activating AMPK, and achieving weight loss, in one intervention.

 

I became interested in this field due to the discussion in:

 

Gruber, J., Fong, S., Chen, C. B., Yoong, S., Pastorin, G., Schaffer, S., ... & Halliwell, B. (2013). Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnology advances, 31(5), 563-592.

In mitochondria, ROS are mainly produced by Complex I, during both forward and reverse electron transport, as well as by Complex III. High mitochondrial ROS production correlates positively with a high mitochondrial membrane potential. In fact, ROS production varies nonlinearly with membrane potential and thus ROS production is highly sensitive to a small decrease in membrane potential. Mitochondrial uncoupling is a process by which proton leak across the mitochondrial inner membrane allows protons to bypass the ATP synthase, thereby preventing electron transport from driving ATP synthesis. Uncoupling o fmitochondria occurs naturally but may be induced by chemical protonophores such as 2,4-dinitrophenol (DNP) and by activating innate mitochondrial uncoupling pathways involving, for instance, uncoupling proteins (UCPs). Dissipation of the mitochondrial membrane potential by mild mitochondrial uncoupling has been shown to significantly reduce ROS production. According to the “uncoupling to survive” hypothesis, partial or mild mitochondrial uncoupling, while maintaining sufficient ATP production, may decrease ROS production, reduce oxidative damage to DNA, proteins and lipids, and may extend lifespan. In support of the “uncoupling to survive” hypothesis, after segregating mice from the same cohort into upper and lower quartiles of metabolic intensities, Speakman et al. found that mitochondria from mice in the upper quartile were more uncoupled, having a higher rate of proton leak and lived 36% longer than mice in the lower quartile. Using noninvasive spectroscopic methods to measure the extent of mitochondrial uncoupling in vivo in two different human muscle types, the tibialis anterior muscle and first dorsal interosseus, of the same human subject, Amara et al. showed that the tibialis anterior muscle, which was mildly uncoupled, had better preserved mitochondrial function and deteriorated less with age than the better coupled first dorsal interosseus. Also, in a comparison of strains of C. elegans carrying lifespan extending mutations, a lower mitochondrial membrane potential was associated with increased worm lifespan and this effect could be replicated using a chemical uncoupler. 

 
I'm currently working my way through:
 
Rial, E., González‐Barroso, M., Fleury, C., Iturrizaga, S., Sanchis, D., Jiménez‐Jiménez, J., ... & Bouillaud, F. (1999). Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2. The EMBO Journal,18(21), 5827-5833.

Serra, F., Bonet, M. L., Puigserver, P., Oliver, J., & Palou, A. (1999). Stimulation of uncoupling protein 1 expression in brown adipocytes by naturally occurring carotenoids. International journal of obesity, 23, 650-655.

Toyomizu, M., Okamoto, K., Ishibashi, T., Chen, Z., & Nakatsu, T. (1999). Uncoupling effect of anacardic acids from cashew nut shell oil on oxidative phosphorylation of rat liver mitochondria. Life sciences, 66(3), 229-234.

Toyomizu, M., Okamoto, K., Ishibashi, T., Nakatsu, T., & Akiba, Y. (2003). Reducing effect of dietary anacardic acid on body fat pads in rats. Animal Science Journal, 74(6), 499-504.Maeda, H., Hosokawa, M., Sashima, T., Funayama, K., & Miyashita, K. (2005). Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues.Biochemical and biophysical research communications, 332(2), 392-397.

Brand, M. D., & Esteves, T. C. (2005). Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell metabolism, 2(2), 85-93.
Amara, C. E., Shankland, E. G., Jubrias, S. A., Marcinek, D. J., Kushmerick, M. J., & Conley, K. E. (2007). Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo. Proceedings of the National Academy of Sciences, 104(3), 1057-1062.
Lou, P., Hansen, B., Olsen, P., Tullin, S., Murphy, M., & Brand, M. (2007). Mitochondrial uncouplers with an extraordinary dynamic range. Biochem. J,407, 129-140.

Caldeira da Silva, CD, Cerqueira, F.M, Barbosa, LF, Medeiros, MH, Kowaltowski, AJ Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging cell. 2008: 7(4), 552-560.

Azzu, V., & Brand, M. D. (2010). The on-off switches of the mitochondrial uncoupling proteins. Trends in biochemical sciences, 35(5), 298-307.
Mookerjee, S. A., Divakaruni, A. S., Jastroch, M., & Brand, M. D. (2010). Mitochondrial uncoupling and lifespan. Mechanisms of ageing and development, 131(7), 463-472.
Hasek, B. E., Stewart, L. K., Henagan, T. M., Boudreau, A., Lenard, N. R., Black, C., ... & Gettys, T. W. (2010). Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 299(3), R728-R739.

Azzu, V., Jastroch, M., Divakaruni, A. S., & Brand, M. D. (2010). The regulation and turnover of mitochondrial uncoupling proteins. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 1797(6), 785-791.

Cerqueira, F. M., Laurindo, F. R., & Kowaltowski, A. J. (2011). Mild mitochondrial uncoupling and calorie restriction increase fasting eNOS, akt and mitochondrial biogenesis. PLoS One, 6(3), e18433.

Divakaruni, A. S., & Brand, M. D. (2011). The regulation and physiology of mitochondrial proton leak. Physiology, 26(3), 192-205.

Ma, S., Yu, H., Zhao, Z., Luo, Z., Chen, J., Ni, Y., ... & Zhu, Z. (2012). Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. Journal of molecular cell biology, 4(2), 88-96.

Yoneshiro, T., Aita, S., Matsushita, M., Kayahara, T., Kameya, T., Kawai, Y., ... & Saito, M. (2013). Recruited brown adipose tissue as an antiobesity agent in humans. The Journal of clinical investigation, 123(123 (8)), 3404-3408.
Bonet, M. L., Oliver, P., & Palou, A. (2013). Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1831(5), 969-985.
McQuaker, S. J., Quinlan, C. L., Caldwell, S. T., Brand, M. D., & Hartley, R. C. (2013). A Prototypical Small‐Molecule Modulator Uncouples Mitochondria in Response to Endogenous Hydrogen Peroxide Production. Chembiochem, 14(8), 993-1000.
Goldgof, M., Xiao, C., Chanturiya, T., Jou, W., Gavrilova, O., & Reitman, M. L. (2014). The Chemical Uncoupler 2, 4-Dinitrophenol (DNP) Protects against Diet-induced Obesity and Improves Energy Homeostasis in Mice at Thermoneutrality. Journal of Biological Chemistry, 289(28), 19341-19350.
Tao, H., Zhang, Y., Zeng, X., Shulman, G. I., & Jin, S. (2014). Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nature medicine.
Perry, R. J., Zhang, D., Zhang, X. M., Boyer, J. L., & Shulman, G. I. (2015). Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science, 347(6227), 1253-1256.
Wanders, D., Burk, D. H., Cortez, C. C., Van, N. T., Stone, K. P., Baker, M., ... & Gettys, T. W. (2015). UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. The FASEB Journal, fj-14
 
Pending controlled release DNP, or commericial MitoBHT, the safest current option appears to be UCP upregulation. Current options for UCP upregulation from Bonet et al 2013 appear to be:
 

β3 adrenergic agonists (mirabegron, solabegron)

PPARγ agonists (benzafibrate, pioglitazone)
AMPK activation (exercise, fasting, metformin, berberine, salicylates, telmisartan, dietary polyphenols)
capsaicin and capsaicin-analogs
fucoxanthin
retinoids
dietary methionine restriction
cold exposure

 


Edited by Darryl, 23 March 2015 - 01:01 AM.

  • Informative x 3
  • Good Point x 1

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#3 pone11

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Posted 23 March 2015 - 02:19 AM

 

Its certainly a fascinating avenue. Reducing mitochondrial ROS generation, activating AMPK, and achieving weight loss, in one intervention.

 

I became interested in this field due to the discussion in:

 

Gruber, J., Fong, S., Chen, C. B., Yoong, S., Pastorin, G., Schaffer, S., ... & Halliwell, B. (2013). Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnology advances, 31(5), 563-592.

...

I'm currently working my way through:

 
Rial, E., González‐Barroso, M., Fleury, C., Iturrizaga, S., Sanchis, D., Jiménez‐Jiménez, J., ... & Bouillaud, F. (1999). Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2. The EMBO Journal,18(21), 5827-5833.

Serra, F., Bonet, M. L., Puigserver, P., Oliver, J., & Palou, A. (1999). Stimulation of uncoupling protein 1 expression in brown adipocytes by naturally occurring carotenoids. International journal of obesity, 23, 650-655.

Toyomizu, M., Okamoto, K., Ishibashi, T., Chen, Z., & Nakatsu, T. (1999). Uncoupling effect of anacardic acids from cashew nut shell oil on oxidative phosphorylation of rat liver mitochondria. Life sciences, 66(3), 229-234.

...

Goldgof, M., Xiao, C., Chanturiya, T., Jou, W., Gavrilova, O., & Reitman, M. L. (2014). The Chemical Uncoupler 2, 4-Dinitrophenol (DNP) Protects against Diet-induced Obesity and Improves Energy Homeostasis in Mice at Thermoneutrality. Journal of Biological Chemistry, 289(28), 19341-19350.

Tao, H., Zhang, Y., Zeng, X., Shulman, G. I., & Jin, S. (2014). Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nature medicine.
Perry, R. J., Zhang, D., Zhang, X. M., Boyer, J. L., & Shulman, G. I. (2015). Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science, 347(6227), 1253-1256.
Wanders, D., Burk, D. H., Cortez, C. C., Van, N. T., Stone, K. P., Baker, M., ... & Gettys, T. W. (2015). UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. The FASEB Journal, fj-14
 
 

 

Thanks for the references.  In what you have read, does anyone put an approximate number on the amount of ATP that is created when you uncouple?



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#4 Darryl

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Posted 23 March 2015 - 03:23 AM

My guess is that ATP production is under regulation and more or less constant. In order to achieve adequate ATP, earlier stages of glycolysis etc are upregulated. In the experiment you reference, that would mean 2.2 times as many calories are expended, with the excess energy dissappated as heat.

 

Fatalities from hyperthermia is the reason 2,4-DNP was banned as a weight loss supplement in the 1930s. Its not clear whether this, or some other aspect of DNP biochemistry, is responsible for the cataract side effect.

 

Toying with mitochondrial uncoupling is like toying with a nuclear chain reactions. That's why I suggest indirect uncoupling via UCP1 etc. as the safer approach, at present. Endogenous uncoupling is probably under better regulation than anything we can achieve at present, though as noted, controlled release DNP or MitoBHT may be attractive (see Lou et al 2007 and Perry et al 2015).


Edited by Darryl, 23 March 2015 - 03:35 AM.

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#5 pone11

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Posted 23 March 2015 - 04:11 AM

My guess is that ATP production is under regulation and more or less constant. In order to achieve adequate ATP, earlier stages of glycolysis etc are upregulated. In the experiment you reference, that would mean 2.2 times as many calories are expended, with the excess energy dissappated as heat.

 

Fatalities from hyperthermia is the reason 2,4-DNP was banned as a weight loss supplement in the 1930s. Its not clear whether this, or some other aspect of DNP biochemistry, is responsible for the cataract side effect.

 

Toying with mitochondrial uncoupling is like toying with a nuclear chain reactions. That's why I suggest indirect uncoupling via UCP1 etc. as the safer approach, at present. Endogenous uncoupling is probably under better regulation than anything we can achieve at present, though as noted, controlled release DNP or MitoBHT may be attractive (see Lou et al 2007 and Perry et al 2015).

 

So a 13% reduction in a mitochondrial membrane gradient would keep ATP production constant while requiring 120% more fuel, which then gets blown off as heat not energy?   That doesn't seem like a great tradeoff....

 

In effect it sounds like the system is spinning out of control.   The body isn't getting the ATP production level it wants, so it revs up the throughput of the electron transport chain, trying in vain to get more ATP production.    

 

Looks pretty non trivial to solve this.



#6 Darryl

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Posted 23 March 2015 - 04:23 AM

It doesn't need to be completely solved. Imagine a pharmaceutical decoupler with a wide dynamic range and hence therapeutic index, and no other side effects.. Perhaps 5-7% potential reductions would offer 50% reductions in mitochondrial ROS production at 150% calorie requirements. That absent ROS may mean a doubling of mitochondrial lifespan. The slight ATP deficit activates AMPK with pluripotent benefits. 

 

That level of decoupling is plausible, probably occurs naturally with some genetic level of UCP expression, and is clearly potentially useful in life extension. The side effects (not being able to endure high temperatures, high hunger) aren't much worse than a number of other anti-aging regimens. 

 

Its not feasible at the moment, mostly because there's no identified safe protonophore with a wide therapeutic index. That can change.

 

 



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#7 Mind

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Posted 25 March 2015 - 06:21 PM

LongeCity funded a study of mitochondrial uncouplers: http://www.longecity...ith-jan-gruber/

 

Also here: http://www.longecity...ial-uncoupling/

 

 







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