Browse > Article
http://dx.doi.org/10.1016/j.jgr.2022.02.002

Major ginsenosides from Panax ginseng promote aerobic cellular respiration and SIRT1-mediated mitochondrial biosynthesis in cardiomyocytes and neurons  

Huang, Qingxia (Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine)
Lou, Tingting (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Lu, Jing (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Wang, Manying (Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine)
Chen, Xuenan (Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine)
Xue, Linyuan (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Tang, Xiaolei (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Qi, Wenxiu (Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine)
Zhang, Zepeng (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Su, Hang (Practice Innovations Center, Changchun University of Chinese Medicine)
Jin, Wenqi (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Jing, Chenxu (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Zhao, Daqing (Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine)
Sun, Liwei (Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine)
Li, Xiangyan (Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine)
Publication Information
Journal of Ginseng Research / v.46, no.6, 2022 , pp. 759-770 More about this Journal
Abstract
Background: Aerobic cellular respiration provides chemical energy, adenosine triphosphate (ATP), to maintain multiple cellular functions. Sirtuin 1 (SIRT1) can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) to promote mitochondrial biosynthesis. Targeting energy metabolism is a potential strategy for the prevention and treatment of various diseases, such as cardiac and neurological disorders. Ginsenosides, one of the major bioactive constituents of Panax ginseng, have been extensively used due to their diverse beneficial effects on healthy subjects and patients with different diseases. However, the underlying molecular mechanisms of total ginsenosides (GS) on energy metabolism remain unclear. Methods: In this study, oxygen consumption rate, ATP production, mitochondrial biosynthesis, glucose metabolism, and SIRT1-PGC-1α pathways in untreated and GS-treated different cells, fly, and mouse models were investigated. Results: GS pretreatment enhanced mitochondrial respiration capacity and ATP production in aerobic respiration-dominated cardiomyocytes and neurons, and promoted tricarboxylic acid metabolism in cardiomyocytes. Moreover, GS clearly enhanced NAD+-dependent SIRT1 activation to increase mitochondrial biosynthesis in cardiomyocytes and neurons, which was completely abrogated by nicotinamide. Importantly, ginsenoside monomers, such as Rg1, Re, Rf, Rb1, Rc, Rh1, Rb2, and Rb3, were found to activate SIRT1 and promote energy metabolism. Conclusion: This study may provide new insights into the extensive application of ginseng for cardiac and neurological protection in healthy subjects and patients.
Keywords
Ginsenosides; Aerobic cellular respiration; Mitochondrial biosynthesis; SIRT1; Cardiomyocytes; Neurons;
Citations & Related Records
Times Cited By KSCI : 5  (Citation Analysis)
연도 인용수 순위
1 Dong G, Chen T, Ren X, Zhang Z, Huang W, Liu L, et al. Rg1 prevents myocardial hypoxia/reoxygenation injury by regulating mitochondrial dynamics imbalance via modulation of glutamate dehydrogenase and mitofusin 2. Mitochondrion 2016;26:7-18.   DOI
2 Hall CN, Klein-Flugge MC, Howarth C, Attwell D. Oxidative phosphorylation, not glycolysis, powers presynaptic and postsynaptic mechanisms underlying brain information processing. J Neurosci 2012;32:8940-51.   DOI
3 Fernie AR, Carrari F, Sweetlove LJ. Respiratory metabolism: glycolysis, the TCA cycle and mitochondrial electron transport. Curr Opin Plant Biol 2004;7: 254-61.   DOI
4 Narne P, Pandey V, Phanithi PB. Interplay between mitochondrial metabolism and oxidative stress in ischemic stroke: an epigenetic connection. Mol Cell Neurosci 2017;82:176-94.   DOI
5 Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 2012;298:229-317.   DOI
6 Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol 2014;24:464-71.   DOI
7 Huang Y, Kwan KKL, Leung KW, Yao P, Wang H, Dong TT, et al. Ginseng extracts modulate mitochondrial bioenergetics of live cardiomyoblasts: a functional comparison of different extraction solvents. J Ginseng Res 2019;43: 517-26.   DOI
8 Canto C, Auwerx J. Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol Rev 2012;64:166-87.   DOI
9 Gonzalez-Burgos E, Fernandez-Moriano C, Lozano R, Iglesias I, Gomez-Serranillos M. Ginsenosides Rd and Re co-treatments improve rotenoneinduced oxidative stress and mitochondrial impairment in SH-SY5Y neuroblastoma cells. Food Chem Toxicol: Int J Publ Brit Ind Biol Res Assoc 2017;109: 38-47.   DOI
10 Hopp AK, Gruter P, Hottiger MO. Regulation of glucose metabolism by NAD(+) and ADP-ribosylation. Cells 2019;8.
11 Ma S, Feng J, Zhang R, Chen J, Han D, Li X, et al. SIRT1 activation by resveratrol alleviates cardiac dysfunction via mitochondrial regulation in diabetic cardiomyopathy mice. Oxid Med Cell Longev 2017;2017:4602715.
12 Aquilano K, Baldelli S, Pagliei B, Ciriolo MR. Extranuclear localization of SIRT1 and PGC-1alpha: an insight into possible roles in diseases associated with mitochondrial dysfunction. Curr Mol Med 2013;13:140-54.   DOI
13 Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA. PPARgamma coactivator-1alpha expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations. Am J Physiol Cell Physiol 2003;284:C1669-77.   DOI
14 Zhou Y, Wang S, Li Y, Yu S, Zhao Y. SIRT1/PGC-1alpha signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats. Front Mol Neurosci 2017;10:443.   DOI
15 Yang JL, Mukda S, Chen SD. Diverse roles of mitochondria in ischemic stroke. Redox Biol 2018;16:263-75.   DOI
16 Zhao XY, Lu MH, Yuan DJ, Xu DE, Yao PP, Ji WL, et al. Mitochondrial dysfunction in neural injury. Front Neurosci 2019;13:30.
17 Huang Q, Lou T, Wang M, Xue L, Lu J, Zhang H, et al. Compound K inhibits autophagy-mediated apoptosis induced by oxygen and glucose deprivation/ reperfusion via regulating AMPK-mTOR pathway in neurons. Life Sci 2020;254:117793.   DOI
18 Liu L, Anderson GA, Fernandez TG, Dore S. Efficacy and mechanism of Panax ginseng in experimental stroke. Front Neurosci 2019;13:294.
19 Jia Y, Zhang S, Huang F, Leung SW. Could ginseng-based medicines be better than nitrates in treating ischemic heart disease? A systematic review and meta-analysis of randomized controlled trials. Compl Ther Med 2012;20: 155-66.   DOI
20 Li X, Huang Q, Wang M, Yan X, Song X, Ma R, et al. Compound K inhibits autophagy-mediated apoptosis through activation of the PI3K-akt signaling pathway thus protecting against ischemia/reperfusion injury. Cell Physiol Biochem 2018;47:2589-601.   DOI
21 Zeiger SL, Stankowski JN, McLaughlin B. Assessing neuronal bioenergetic status. Methods Mol Biol 2011;758:215-35.   DOI
22 Tang Y, Luo B, Deng Z, Wang B, Liu F, Li J, et al. Mitochondrial aerobic respiration is activated during hair follicle stem cell differentiation, and its dysfunction retards hair regeneration. PeerJ 2016;4:e1821.   DOI
23 De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 2013;154:651-63.   DOI
24 Canto C, Menzies KJ, Auwerx J. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metabol 2015;22:31-53.   DOI
25 Wang JR, Zhou H, Yi XQ, Jiang ZH, Liu L. Total ginsenosides of Radix Ginseng modulates tricarboxylic acid cycle protein expression to enhance cardiac energy metabolism in ischemic rat heart tissues. Molecules 2012;17: 12746-57.   DOI
26 Zhu H, Toan S, Mui D, Zhou H. Mitochondrial quality surveillance as a therapeutic target in myocardial infarction. Acta Physiol 2021;231:e13590.
27 Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 2012;22:66-79.   DOI
28 Katsyuba E, Mottis A, Zietak M, De Franco F, van der Velpen V, Gariani K, et al. De novo NAD(+) synthesis enhances mitochondrial function and improves health. Nature 2018;563:354-9.   DOI
29 Chang CN, Singh AJ, Gross MK, Kioussi C. Requirement of Pitx2 for skeletal muscle homeostasis. Dev Biol 2019;445:90-102.   DOI
30 John S, Weiss JN, Ribalet B. Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS One 2011;6:e17674.   DOI
31 Fillmore N, Lopaschuk GD. Targeting mitochondrial oxidative metabolism as an approach to treat heart failure. Biochim Biophys Acta 2013;1833:857-65.   DOI
32 Yang XW, Ma LY, Zhou QL, Xu W, Zhang YB. SIRT1 activator isolated from artificial gastric juice incubate of total saponins in stems and leaves of Panax ginseng. Bioorg Med Chem Lett 2017.
33 Yepez VA, Kremer LS, Iuso A, Gusic M, Kopajtich R, Konarikova E, et al. OCRStats: robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer. PLoS One 2018;13:e0199938.   DOI
34 Algarve TD, Assmann CE, Aigaki T, da Cruz IBM. Parental and preimaginal exposure to methylmercury disrupts locomotor activity and circadian rhythm of adult Drosophila melanogaster. Drug Chem Toxicol 2020;43:255-65.   DOI
35 Han Q, Han L, Tie F, Wang Z, Ma C, Li J, et al. (20S)-Protopanaxadiol ginsenosides induced cytotoxicity via blockade of autophagic flux in HGC-27 cells. Chem Biodivers 2020;17:e2000187.
36 Wang Y, Liang X, Chen Y, Zhao X. Screening SIRT1 activators from medicinal plants as bioactive compounds against oxidative damage in mitochondrial function. Oxid Med Cell Longev 2016;2016:4206392.
37 Hickey AJ, Chai CC, Choong SY, de Freitas Costa S, Skea GL, Phillips AR, et al. Impaired ATP turnover and ADP supply depress cardiac mitochondrial respiration and elevate superoxide in nonfailing spontaneously hypertensive rat hearts. Am J Physiol Cell Physiol 2009;297:C766-74.   DOI
38 Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 2012;337:96-100.   DOI
39 Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab 2003;284:E855-62.
40 Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol 2010;5:297-348.   DOI
41 Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 2019;20:148-60.   DOI
42 Xu M, Ma Q, Fan C, Chen X, Zhang H, Tang M. Ginsenosides Rb1 and Rg1 protect primary cultured astrocytes against oxygen-glucose deprivation/ reoxygenation-induced injury via improving mitochondrial function. Int J Mol Sci 2019;20.
43 Wheaton WW, Chandel NS. Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol 2011;300:C385-93.   DOI
44 Aravinthan A, Kim JH, Antonisamy P, Kang CW, Choi J, Kim NS, et al. Ginseng total saponin attenuates myocardial injury via anti-oxidative and antiinflammatory properties. J Ginseng Res 2015;39:206-12.   DOI
45 Wu T, Kwaku OR, Li H-Z, Yang C-R, Ge L-J, Xu M. Sense ginsenosides from ginsengs: structure-activity relationship in autophagy. Nat Prod Commun 2019;14.
46 Yang YL, Li J, Liu K, Zhang L, Liu Q, Liu B, et al. Ginsenoside Rg5 increases cardiomyocyte resistance to ischemic injury through regulation of mitochondrial hexokinase-II and dynamin-related protein 1. Cell Death Dis 2017;8:e2625.   DOI
47 Chen X, Wang Q, Shao M, Ma L, Guo D, Wu Y, et al. Ginsenoside Rb3 regulates energy metabolism and apoptosis in cardiomyocytes via activating PPARalpha pathway. Biomed Pharmacother 2019;120:109487.   DOI
48 Sun M, Huang C, Wang C, Zheng J, Zhang P, Xu Y, et al. Ginsenoside Rg3 improves cardiac mitochondrial population quality: mimetic exercise training. Biochem Biophys Res Commun 2013;441:169-74.   DOI