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.
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.
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.
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.
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.