The role of PGC-1α in mitochondrial transcription factors: A promising pathway in the treatments of mitochondrial diseases activated by Gynostemma pentaphyllum


The role of PGC-1α in mitochondrial transcription factors: A promising pathway in the treatments of mitochondrial diseases activated by Gynostemma pentaphyllum


Ferro M., Channan G.

FG Scientifica and Science Department at Nutrition Formulators Inc., Miramar, Fl, 3260 Executive way, Parkway, Miramar, Fl 33025 Miramar, Fl, USA.


The peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), being a key transcription factor in mitochondrial biogenesis, interacts as a coactivator of several mitochondrial nuclear transcription factors, such as nuclear respiratory factor (NRF) 1 and 2, estrogen-related receptor α (ERRα), as well as non-nuclear receptor myocyte-enhancing factor 2 (MEF-2). Gynostemma pentaphyllum (GP) is a plant used in many countries, mainly in Asia, having strong activity in PGC-1α. A wide range of GP pharmacological properties has been reported, including anti-inflammatory and antioxidant activity, lipid metabolism modulator, and neuroprotective activity. The activation of PGC-1α by exogenous factors has become a promising strategy in the treatment of various pathologies, especially when focused on mitochondria. In our review, we found numerous benefits of GP in controlling age-associated metabolic diseases, mainly in diabetes type 2, fat liver, and obesity. Some studies have also reported that, due to the strong phosphorylation of AMP protein kinase (AMPK) exerted by GP, GP-treated mice showed a significant increase in Sirtuin 1 (SIRT1) mRNA expression, a protein that acts directly on cellular aging processes. However, further studies in humans could provide more proof of its efficiency in diseases such as metabolic syndrome as well as any other pathology that involves changes in mitochondrial functions.


Keywords: Gynostemma pentaphyllum, PCG-1α, mitochondria, AMPK, SIRT1, metabolic syndrome.

Free Full-text PDF


How to cite this article:

Ferro M., Channan G. The role of PGC-1α in mitochondrial transcription factors: A promising pathway in the treatments of mitochondrial diseases activated by Gynostemma pentaphyllum. International Journal of Food and Nutrition Research, 2022; 6:47. DOI:10.28933/ijfnr-2022-06-1805fmcg


References:

1. WU Z, PUIGSERVER P, ANDERSSON U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98:115–124.
2. LIANG H, and WARD WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. 2006 Dec;30(4):145-51.
3. FINCK BN, and KELLY DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest. 2006 Mar 1; 116(3): 615–622.
4. COLLU-MARCHESE M, SHUEN M, PAULY M, et al. The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation. Biosci Rep. 2015 Jun; 35(3): e00221.
5. PUIGSERVER P, WU Z, PARK CW, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92: 829–839, 1998.
6. JØRGENSEN SB, RICHTER EA, and WOJTASZEWSKI JFP. The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation. Biosci Rep. 2015 Jun; 35(3): e00221.
7. JÄGER S, HANDSCHIN C, ST-PIERRE J, et al. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. U.S.A. 2007;104:12017–12022.
8. BERGERON R, REN JM, CADMAN KS, et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. Endocrinol. Metab. 2001;281:E1340–E1346.
9. GARCIA-ROVES PM, OSLER ME, HOLMSTRÖM MH, et al. Gain-of-function R225Q mutation in AMP-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J. Biol. Chem. 2008;283:35724–35734.
10. WINDER WW, and HARDIE DG. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol. 1996;270:E299–E304.
11. FUJII N, HAYASHI T, HIRSHMAN MF, et al. Exercise induces isoform-specific increase in 5′AMP-activated protein kinase activity in human skeletal muscle. Biochem Biophys Res Commun. 2000;273:1150–1155.
12. JORNAYVAZ FR and SHULMAN GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010; 47: 10.1042/bse0470069.
13. CALEGARI VC, ZOPPI CC, REZENDE LF, et al. Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2, and reduces insulin secretion from rat pancreatic islets. J Endocrinol. 2011 Mar;208(3):257-64.
14. WU Z, HUANG X, FENG Y, et al. Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells. Proc Natl Acad Sci USA. 2006 Sep 26;103(39):14379-84.
15. TSAI W, NIESSEN S, GOEBEL N, et al. PRMT5 modulates the metabolic response to fasting signals. Proc Natl Acad Sci U S A. 2013 May 28;110(22):8870-5.
16. XU Z, LIU J, YOU W, et al. Cold exposure induces nuclear translocation of CRTC3 in brown adipose tissue. J Cell Biochem. 2019 Jun;120(6):9138-9146.
17. LEE HS, LIM S, JUNG JI, et al. Gynostemma Pentaphyllum Extract Ameliorates High-Fat Diet-Induced Obesity in C57BL/6N Mice by Upregulating SIRT1. Nutrients. 2019 Oct 15;11(10):2475.
18. CHEN S, and JEFFREY C. “Gynostemma Blume, Bijdr. 23. 1825”. Flora of China. Missouri Botanical Garden, St. Louis, MO & Harvard University Herbaria, Cambridge, MA. Retrieved 2 May 2018.
19. LI Y, LIN W, HUANG J, et al. Anti-cancer effects of Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan). Chin Med. 2016; 11: 43.
20. YANG F, SHI H, ZHANG X, et al. Two new saponins from tetraploid jiaogulan (Gynostemma pentaphyllum), and their anti-inflammatory and α-glucosidase inhibitory activities. Food Chem. 2013;141:3606–3613.
21. ZHAO J, MING Y, WAN Q, et al. Gypenoside attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative and anti-apoptotic bioactivities. Exp Ther Med. 2014;7:1388–1392.
22. LI B, ZHANG XY, WANG MZ, et al. Characterization and antioxidant activities of acidic polysaccharides from Gynostemma pentaphyllum (Thunb.) Markino. Carbohydr Polym. 2015;127:209–214.
23. QIN R, ZHANG J, LI C, ZHANG X, et al. Protective effects of gypenosides against fatty liver disease induced by high fat and cholesterol diet and alcohol in rats. Arch Pharm Res. 2012;35:1241–1250.
24. TSUI K-C, CHIANG T-H, WANG J-S, et al. Flavonoids from Gynostemma pentaphyllum exhibit differential induction of cell cycle arrest in H460 and A549 cancer cells. Molecules. 2014;19:17663–17681. doi: 10.3390/molecules191117663.
25. HE Q, LI JK, LI F, et al. Mechanism of action of gypenosides on type 2 diabetes and non-alcoholic fatty liver disease in rats. World J Gastroenterol. 2015;21:2058–2066.
26. GAO D, ZHAO M, QI X, et al. Hypoglycemic effect of Gynostemma pentaphyllum saponins by enhancing the nrf2 signaling pathway in stz-inducing diabetic rats. Arch Pharm Res. 2016;39:221–230.
27. HUANG TH, TRAN VH, ROUFOGALIS BD, et al. Gypenoside XLIX, a naturally occurring gynosaponin, PPAR-alpha dependently inhibits LPS-induced tissue factor expression and activity in human THP-1 monocytic cells. Toxicol Appl Pharmacol. 2007 Jan 1;218(1):30-6.
28. YAN H, WANG X, NIU J, et al. Anti-cancer effect and the underlying mechanisms of gypenosides on human colorectal cancer SW-480 cells. PLoS One. 2014;9:e95609.
29. HOU J, LIU S, MA Z, et al. Effects of Gynostemma pentaphyllum Makino on the immunological function of cancer patients. J Tradit Chin Med. 1991;11:47–52.
30. SU C, LI N, REN R, et al. Progress in the Medicinal Value, Bioactive Compounds, and Pharmacological Activities of Gynostemma pentaphyllum. Molecules. 2021 Oct; 26(20): 6249.
31. ZHANG T, and YUAN, DS. Advances in Studies on Gynostemma Germplasm Resources in China. J. Yunnan Agric. Univ. 2009, 24, 459–461.
32. RAZMOVSKI-NAUMOVSKI V, HUANG TH, TRAN VH, et al. Chemistry and Pharmacology of Gynostemma pentaphyllum. Phytochem. Rev. 2005;4:197–219.
33. PARK S, HUH T, KIM S, et al. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): A randomized, double-blind, placebo-controlled trial. Obesity(2014)22, 63–71.
34. CARLING D. The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem Sci 2004;29:18-24.
35. HARDIE DG. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes (Lond) 2008;32(Suppl 4):S7-S12.
36. LI W, SAUD SM, YOUNG MR, et al. Targeting AMPK for cancer prevention and treatment. Oncotarget. 2015 Apr 10; 6(10): 7365–7378.
37. HERZIG S, and SHAW RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nature Reviews Molecular Cell Biology volume 19, pages121–135 (2018).
38. NGUYEN PH, GAUHAR R, HWANG SL, et al. New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum. Bioorg Med Chem 2011;19:6254-6260.
39. CANTÓ C, and AUWERX J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009 Apr; 20(2): 98–105.
40. MICHAEL LF, WU Z, CHEATHAM RB, et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci U S A. 2001;98:3820–5.
41. PUIGSERVER P, RHEE J, DONOVAN J, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003;423:550–5.
42. VEGA RB, HUSS JM, and KELLY DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000;20:1868–76.
43. WANG YX, LEE CH, TIEP S, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell. 2003;113:159–70.
44. HEN W, YANG Q, and ROEDER RG. Dynamic interactions and cooperative functions of PGC-1α and MED1 in TRα-mediated activation of the brown fat-specific UCP-1 gene. Mol Cell. 2009 Sep 24; 35(6): 755–768.
45. CHENG C, KU H, and LIN H. PGC-1α as a Pivotal Factor in Lipid and Metabolic Regulation. Int J Mol Sci. 2018 Nov; 19(11): 3447.
46. MILLER KN, JOSEF P. CLARK JP, and ANDERSON RM. Mitochondrial regulator PGC-1a-Modulating the modulator. Curr Opin Endocr Metab Res. 2019 Mar; 5: 37–44.
47. HUYEN VTT, PHAN DV, THANG P, et al. Gynostemma pentaphyllum Tea Improves Insulin Sensitivity in Type 2 Diabetic Patients. J Nutr Metab. 2013; 2013: 765383.
48. KJØBSTED R, HINGST JR FENTZ J, et al. AMPK in skeletal muscle function and metabolism. FASEB J. 2018 Apr; 32(4): 1741–1777.
49. ESCHBACH J, VON EINEM B, MÜLLER K, et al. Mutual exacerbation of PGC-1α deregulation and α-synuclein oligomerization. Ann Neurol. 2015 Jan; 77(1): 15–32.
50. KIM YH, JUNG JI, JEON YE, et al. Gynostemma pentaphyllum extract and Gypenoside L enhance skeletal muscle differentiation and mitochondrial metabolism by activating the PGC-1α pathway in C2C12 myotubes. Nutr Res Pract. 2022 Feb; 16(1): 14–32.
51. KOSKI RR, “Practical review of oral antihyperglycemic agents for type 2 diabetes mellitus,” Diabetes Educator, vol. 32, no. 6, pp. 869–876, 2006.
52. YEH GY, EISENBERG DM, KAPTCHUK TJ, et al. “Systematic review of herbs and dietary supplements for glycemic control in diabetes,” Diabetes Care, vol. 26, no. 4, pp. 1277–1294, 2003.
53. HUYEN VTT, PHAN DV, THANG P, et al. “Antidiabetic effect of add-on Gynostemma pentaphyllum tea therapy with sulfonylureas in randomly assigned type 2 diabetic patients,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 452313, 7 pages, 2012.
54. QIFA YE, YI ZHU, SHAOJUN YE, et al. Gypenoside attenuates renal ischemia/reperfusion injury in mice by inhibition of ERK signaling. Exp Ther Med. 2016 Apr; 11(4): 1499–1505.
55. NORBERG Å, HOA NK, LIEPINSH E, et al. Novel Insulin-releasing Substance, Phanoside, from the Plant Gynostemma pentaphyllum. J. Biol. Chem. 2004;279:41361–41367.
56. SATO Y, and HENQUIN JC. The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose: in search of the underlying mechanism. Diabetes. 1998 Nov;47(11):1713-21.
57. HOA NK, NORBERG A, SILLARD R, et al. The possible mechanisms by which phanoside stimulates insulin secretion from rat islets. J. Endocrinol. 2007;192:389–394.
58. CHAO SU C, NAN LI N, REN R, et al. Progress in the Medicinal Value, Bioactive Compounds, and Pharmacological Activities of Gynostemma pentaphyllum. Molecules. 2021 Oct; 26(20): 6249.
59. LUNDQVIST LCE, RATTIGAN D, EHTESHAM E, et al. Profiling and activity screening of Dammarane-type triterpen saponins from Gynostemma pentaphyllum with glucose-dependent insulin secretory activity. Sci Rep. 2019; 9: 627.
60. HESSE C, RAZMOVSKI-NAUMOVSKI V, DUKE CC, et al. Phytopreventative effects of Gynostemma pentaphyllum against acute Indomethacin-induced gastrointestinal and renal toxicity in rats. Phytother Res. 2007 Jun;21(6):523-30.
61. SRIVASTAVA RAK, PINKOSKY SL, FILIPPOV S et al. AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases. J Lipid Res. 2012 Dec; 53(12): 2490–2514.
62. WEBSTER I. AMP kinase activation and glut4 translocation in isolated cardiomyocytes. Cardiovasc J Afr. 2010 Apr; 21(2): 72–78.
63. GAUHAR R, HWANG S, JEONG S, et al. Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase. Biotechnol. Lett. 2012;34:1607–1616.
64. LIU J, LI YF, YANG PY, et al. Gypenosides reduced the risk of overweight and insulin resistance in C57BL/6J mice through modulating adipose thermogenesis and gut microbiota. J. Agric. Food Chem. 2017;65:9237–9246.
65. RAO A, CLAYTON P, and BRISKEY D. The effect of an orally-dosed Gynostemma pentaphyllum extract (ActivAMP®) on body composition in overweight, adult men and women: A double-blind, randomized, placebo-controlled study. J Hum Nutr Diet. 2022;35:583–589.
66. TOSATO M, ZAMBONI V, FERRINI A, et al. The aging process and potential interventions to extend life expectancy. Clin Interv Aging. 2007 Sep; 2(3): 401–412.
67. NITA M and GRZYBOWSKI A. The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults. Oxid Med Cell Longev. 2016; 2016: 3164734.
68. PHANIENDRA A, JESTADI DB, and PERIYASAMY L. Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases. Indian J Clin Biochem. 2015 Jan; 30(1): 11–26.
69. Guo C, Sun L, Chen X, et al. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013 Jul 25; 8(21): 2003–2014.
70. BORODKINA A, SHATROVA A, ABUSHIK P, et al. Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells. Aging (Albany NY). 2014 Jun; 6(6): 481–495.
71. MACIP S, IGARASHI M, BERGGREN P, et al. Influence of Induced Reactive Oxygen Species in p53-Mediated Cell Fate Decisions. Mol Cell Biol. 2003 Dec; 23(23): 8576–8585.
72. GRABOWSKA W, SIKORA E, and BIELAK-ZMIJEWSKA A. Sirtuins, a promising target in slowing down the ageing process. Biogerontology. 2017; 18(4): 447–476.
73. ZHAO L, CAO J, HU K, et al. Sirtuins and their Biological Relevance in Aging and Age-Related Diseases. Aging Dis. 2020 Jul; 11(4): 927–945.
74. SERGI C, SHEN F, and LIU S. Insulin/IGF-1R, SIRT1, and FOXOs Pathways—An Intriguing Interaction Platform for Bone and Osteosarcoma. Front Endocrinol (Lausanne). 2019; 10: 93.
75. HAIGIS MC and SINCLAIR DA. Mammalian Sirtuins: Biological Insights and Disease Relevance. Annu Rev Pathol. 2010; 5: 253–295.
76. PRICE NL, GOMES AP, LING AJY, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012 May 2; 15(5): 675–690.
77. RUDERMAN NB, XU XJ, NELSON L, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010 Apr; 298(4): E751–E760.
78. LOU Y, ZHENG X, HUANG Y, et al. New dammarane-type triterpenoid saponins from Gynostemma pentaphyllum and their Sirt1 agonist activity. Bioorg Chem. 2021 Nov;116:105357.


Terms of Use/Privacy Policy/ Disclaimer/ Other Policies:
You agree that by using our site/services, you have read, understood, and agreed to be bound by all of our terms of use/privacy policy/ disclaimer/ other policies (click here for details)


CC BY 4.0
This work and its PDF file(s) are licensed under a Creative Commons Attribution 4.0 International License.