Mild Uncoupling of Oxidative Phosphorylation and Prospects of Its Use in Medicine (Review)
DOI:
https://doi.org/10.14738/jbemi.94.12650Keywords:
uncoupling thermogenesis oxidative stress mild uncouplers use in medicineAbstract
The review summarizes and analyzes modern data about the structure and mechanism of action of endogenous and exogenous substances that have been able to uncouple softly oxidative phosphorylation from respiration in mitochondria of various body tissues. The data on the effect of mild uncouplers on the redistribution of hydrogen ions on both sides of the inner mitochondrial membrane and the value of the proton membrane potential are systematized. Evidence of a decrease in the level of reactive oxygen species under the action of these substances is given. Typical physiological effects that develop as a result of the action of mild uncouplers (thermogenesis, prevention of mito- and apoptosis) are described. Possible ways of using these substances as drugs for the prevention and treatment of obesity, cardiovascular, neurodegenerative, inflammatory and oncological diseases are discussed.
References
Ježek P., Holendová B., Plecitá-Hlavatá L. Redox Signaling from Mitochondria: Signal Propagation and Its Targets. Biomolecules. 2020; 10(1): 93. Published online 2020 Jan 6. doi: 10.3390/biom10010093
Venditti P., and Di Meo S. The Role of Reactive Oxygen Species in the Life Cycle of the Mitochondrion. Int J Mol Sci. 2020; 21(6): 2173. Published online 2020 Mar 21. doi: 10.3390/ijms21062173
Swerdlow N.S., and Wilkins H.M. Mitophagy and the Brain. Int J Mol Sci. 2020; 21(24): 9661. Published online 2020 Dec 18. doi: 10.3390/ijms21249661
Venditti P., and Di Meo S. The Role of Reactive Oxygen Species in the Life Cycle of the Mitochondrion. Int. J. Mol. Sci. 2020; 21:2173 doi: 10.3390/ijms21062173
Lomonosova, E., Ryerse J., and Chinnadurai G. BAX/BAK–Independent Mitoptosis during Cell Death Induced by Proteasome Inhibition? Mol Cancer Res. 2009; 7(8): 1268–84 doi: 10.1158/1541-7786.MCR-08-0183
Berrya, B.J., et al., Use the protonmotive force: mitochondrial uncoupling and reactive oxygen species. J Mol Biol. 2018 October 19; 430(21): 3873–3891 doi: 10.1016/j.jmb.2018.03.025
Zorova, L.D., et al., Mitochondrial membrane potential. Anal Biochem. 2018; 1,552:50-59 doi: 10.1016/j.ab.2017.07.009
Khailova, L.S., et al., Interaction of Potent Mitochondrial Uncouplers with Thiol-Containing Antioxidants. Antioxidants (Basel) 2019 Jun; 8(6): 194. Published online 2019 Jun 23. doi: 10.3390/antiox8060194
Geisler, J.G., et al., DNP, Mitochondrial Uncoupling and Neuroprotection: A Little Dab’ll Do Ya. Alzheimers Dement. 2017; 13(5): 582–591 doi: 10.1016/j.jalz.2016.08.001
Geisler, J.G. 2,4 Dinitrophenol as Medicine. Cells 2019, 8, 280; 1-36 doi: 10.3390/cells8030280
Pozdnyakov D.I. 4-Hydroxy-3,5-di-tret-butyl cinnamic acid restores the activity of the hippocampal mitochondria in rats under permanent focal cerebral ischemia. Iran J Basic Med Sci. 2021 Nov; 24(11): 1590–1601. doi: 10.22038/IJBMS.2021.58435.12979
Zholobenko, A.V., et al., On the causes and consequences of the uncoupler-like effects of quercetin and dehydrosilybin in H9c2 cells. PLOS ONE. 2017; https://doi.org/10.1371/journal.pone.0185691 October 4, 1-22
Skulachev, V.P. Cationic antioxidants as a powerful tool against mitochondrial oxidative stress. Biochem Biophys Res Commun. 2013; 15;441(2):275-9
Severina F.P., et al., Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. PNAS January 12, 2010; 107, 2, 663–668 doi: 10.1073/pnas.0910216107
Ardalan, A., Smith, M.D., Jelokhani-Niaraki M. Uncoupling Proteins and Regulated Proton Leak in Mitochondria. Int. J. Mol. Sci. 2022; 23, 1528. https://doi.org/10.3390/ijms23031528
Plotnikov, E.Y., et al., A new generation of Skulachev ions possessing apparent nephro- and neuroprotective propertioes. Biochemistry (Mosc). 2010; 75 (2):177-85
Tejerina1, S., et al., Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differentiation by a PPARγ-independent mechanism, whereas TNFα-induced de-differentiation is PPARγ dependent. J Cell Sci 2009;
Urra, F.A., et al., FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway. Scientific Reports. 2018; 8:13190 | doi:10.1038/s41598-018-31367-9
Jaburek, M., et al., Antioxidant Synergy of Mitochondrial Phospholipase PNPLA8/iPLA2γ with Fatty Acid–Conducting SLC25 Gene Family Transporters. Antioxidants. 2021; 10: 678. https://doi.org/10.3390/antiox10050678
Ruiz-Ramírez, A., et al., Cell Death and Heart Failure in Obesity: Role of Uncoupling Proteins. Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2016, Article ID 9340654, 11 pages http://dx.doi.org/10.1155/2016/9340654
Zorov, D.B., et al., Neuroprotective Potential of Mild Uncoupling in Mitochondria. Pros and Cons. Brain Sci. 2021, 11, 1050. https://doi.org/10.3390/brainsci11081050
Skulachev, V.P., Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett. 1991; 294: 158–162
Jezˇek, P., et al., Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling. Antioxidants & Redox signaling. 2017; 29, 7: 667-714 doi: 10.1089/ars.2017.7225
Maslov, L.N., Vychuzhanina, E.A., Role of sympatho-adrenomedullar system in adaptation to cold [Article in Russian]. Ross Fiziol Zh Im I M Sechenova. 2015; 101(2):145-62.
Demine, S. , Renard, P., and Arnould, T., Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases. Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases. Cells. 2019; 8, 795 doi: 10.3390/cells8080795
Teodoro, J.S., et al., J. Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice. Int J of Obesity. 2014; 1–8
Zietak, M., and Kozak L.P., Bile acids induce uncoupling protein 1-dependent thermogenesis and stimulate energy expenditure at thermoneutrality in mice. Am J Physiol Endocrinol Metab. 2016; 310(5): 346–54 doi: 10.1152/ajpendo.00485.2015
Chiang, J.Y.A., Bile Acid Metabolism and Signaling. Compr Physiol. 2013; 3(3): 1191–1212
Tiangang, Li, Chiang J.Y.A., Bile acids as metabolic regulators. Curr Opin Gastroenterol. 2015; 31(2): 159–165 doi: 10.1097/MOG.0000000000000156
Chiang, J. Y. L., Bile acid metabolism and signaling. Compr Physiol. 2013 July ; 3(3): 1191–1212
Jones, M.L., et al., The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention. Expert Opin. Biol. Ther. 2014; 14(4): 467-82
Li, T., Chiang, J. Y. L., Bile acids as metabolic regulators. Curr Opin Gastroenterol. 2015; 31(2): 159–65
Zagoskin, P.P., and Erlykina, E.I., Bile Acids as a New Type of Steroid Hormones Regulating Nonspecific Energy Expenditure of the Body (Review). Sovrem Tekhnologii Med. 2021; 12, 5: 114-28. doi: 10.17691{stm2020.12.5.13
Quad de Aguiar, T.V., and Edwards, P.A., Bile Acids Have the Gall to Function as Hormones. Cell Metabolism. 2009; 10, 2: 162-64
Joyce, S.A., Gahan, C.G.M., Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota. Dig Dis 2017; 35:169–177
D’Amore, C., et al., Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors J. Med. Chem. 2014; 57: 937−54
Krasowskia, M.D., Nib, A., Hageyc, L.R., and Ekins, S., Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR. Mol Cell Endocrinol. 2011; 334(1-2): 39–48.
Cong, Xie,, et al., Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease. Nutrients 2021, 13, 1104. https://doi.org/10.3390/nu13041104 143
Zagoskin, P.P., Nonspecific Energy Expenditure of the Body and Body Mass Regulation. J Nutri Bio. 2019; 5(1): 328-49
Pournaras, D. J., and le Roux, C. W., Are Bile Acids the New Gut Hormones? Lessons From Weight Loss Surgery Models. Endocrinology. 2013; 154(7): 2255–56
de Pascual-Teresa, S., Moreno, D.A., and García-Viguera, C., Flavanols and Anthocyanins in Cardiovascular Health: A Review of Current Evidence. Int. J. Mol. Sci. 2010; 11: 1679-1703
Surai, P.F., Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives. Antioxidants. 2015; 4: 204-247
Ishii, Y., et al., Repeated Oral Administration of Flavan-3-ols Induces Browning in Mice Adipose Tissues through Sympathetic Nerve Activation. Nutrients 2021; 13, 4214. doi.org/10.3390/nu13124214
Xuejun, Zhang., et al., Flavonoids as inducers of white adipose tissue browning and thermogenesis: signalling pathways and molecular triggers. Zhang et al. Nutrition & Metabolism 2019; 16:47 doi.org/10.1186/s12986-019-0370-7
Aziz, S.A., et al., Metabolic programming of a beige adipocyte phenotype by genistein. Mol. Nutr. Food Res. 2017; 61, 2: 1600574
Hye Won Kang, Sang Gil Lee, Otieno D., and Kyoungsoo Ha.,. Flavonoids, Potential Bioactive Compounds, and Non-Shivering Thermogenesis. Nutrients 2018; 10: 1168
Rebello, C., et al.,Naringenin Promotes Thermogenic Gene Expression in Human White Adipose Tissue. Obesity (Silver Spring). 2019; 27(1): 103–11
Jing Dong., et al.,Quercetin reduces obesity-associated ATM infiltration and infl ammation in mice: a mechanism including AMPK 1/SIRT1. Journal of Lipid Research. 2014; 55: 363-74
Un Ju Jung., Yun-Young Cho., and Myung-Sook Choi., Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice. Nutrients. 2016; 8(5): 305.
Aguirre, L., et al., Resveratrol: Anti-Obesity Mechanisms of Action. Mol. 2014; 19: 18632-55
Rai, S.N., et al., The Role of Vitamins in Neurodegenerative Disease: An Update. Biomedicines. 2021; 9, 1284.doi.org/10.3390/biomedicines9101284
Blaner, W.S., Vitamin A Signaling and Homeostasis in Obesity, Diabetes, and Metabolic Disorders. Pharmacol Ther. 2019; 197: 153–78.
Nishida, Y., et al., Astaxanthin as a Novel Mitochondrial Regulator: A New Aspect of Carotenoids, beyond Antioxidants. Nutrients 2022; 14, 107. doi.org/10.3390/nu14010107
Gammone, M.A., Riccioni, G., and D’Orazio, N., Carotenoids: potential allies of cardiovascular health? Food & Nutrition Research. 2015; 59: 26762 - doi.org/10.3402/fnr.v59.26762
Toshiyuki Suzuki, et al., Weight Loss by Ppc-1, a Novel Small Molecule Mitochondrial Uncoupler Derived from Slime Mold. PLOS ONE. 2015; February 10| DOI:10.1371/journal.pone.0117088
Zielonka, J., et al., Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chem Rev. 2017 August 09; 117(15): 10043–10120
Apostolova, N., and Victor, V.M., Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications. Antiox Redox Signal. 2015 Mar 10; 22(8): 686–729
Sharma, A., et al., Targeting Mitochondrial Dysfunction and Oxidative Stress in Activated Microglia using Dendrimer-Based Therapeutics. 2018; 8(20): 5529-5547. doi: 10.7150/thno.29039
Blaikie Frances, H., et al., Targeting Dinitrophenol to Mitochondria: Limitations to the Development of a Selflimiting Mitochondrial Protonophore. Biosci Rep (2006) 26:231–43 144
Severin, F.F., et al., Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc Natl Acad Sci U S A. 2010; 107(2): 663–68
Anisimov, V.N., et al., Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. Biochemistry (Mosc). 2008; 73,12: 1655 –70
Isaev, N.K., et al., Alzheimer's Disease: An Exacerbation of Senile Phenoptosis. Biochemistry (Mosc). 2015;;80(12):1578-81. doi: 10.1134/S0006297915120056.
Korshunova,G.A., Shishkina, A.V., and Skulachev, M.V., Design, Synthesis, and Some Aspects of the Biological Activity of Mitochondria-Targeted Antioxidants. Biochemistry (Mosc). 2017; Jul;82(7):760-777. doi: 10.1134/S0006297917070021.
Stanforda, K.I., and Goodyear, L.J., Exercise regulation of adipose tissue. Adipocyte. 2016; 5(2): 153–62
Dewal R.S., Stanford K.I. Effects of exercise on brown and beige adipocytes. Biochim Biophys Acta Mol Cell Biol Lipids. 2019; 1864(1): 71–78
Jae Ho Le., et al., The Role of adipose tissue mitochondria: regulation of mitochondrial function for the treatment of metabolic diseases. Int. J. Mol. Sci. 2019, 20, 4924; doi:10.3390/ijms20194924
van der Lans, A.A.J.J., et al., Cold acclimation recruits brown fat and increases nonshivering thermogenesis. The Journal of Clinical Investigation .Volume 123 Number 8 August 2013
Dempersmier, J., et al., Cold–inducible Zfp516 Activates UCP1 Transcription to Promote Browning of White Fat and Development of Brown Fat. Mol Cell. 2015; 22, 57(2): 235–46
Chen, K.Y., et al., Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity. J. Biol. Chem. (2020) 295(7) 1926 –42
Maiese, K., New Insights for Oxidative Stress and Diabetes Mellitus. Oxid Med Cell Longev. 2015; 2015: 875961. Published online 2015 May 12. doi: 10.1155/2015/875961
Dang, C.P., et al., BAM15, a Mitochondrial Uncoupling Agent, Attenuates Inflammation in the LPS Injection Mouse Model: An Adjunctive Anti-Inflammation on Macrophages and Hepatocytes. Innate Immun. 2021; 13(6): 359–75. Published online 2021 Jun 1. doi: 10.1159/000516348
Jurcau, A., and Ardelean, A.I., Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke. Biomedicines. 2022; 10(3): 574. Published online 2022 Mar 1. doi: 10.3390/biomedicines10030574
Shrestha, R., Johnson, E., and Byrne F.L., Exploring the therapeutic potential of mitochondrial uncouplers in cancer. Molecular metabolism. 2021; 51: 101222 _ 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Perez-Pinzon, M.A., Stetler, R.A., and Fiskum G., Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab. 2012; 32(7): 1362–76.
Seyyed Hossein Hassanpour, Mohammad Amin Dehghani, and Seyyedeh Zeinab Karami., Study of respiratory chain dysfunction in heart disease. J Cardiovasc Thorac Res. 2018; 10(1): 1–13. Published online 2018 Mar 17. doi: 10.15171/jcvtr.2018.01
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