Vol. 4 No. 1 (2021): International Journal of Aging Research
Review Articles

Mitochondrial Metabolism, Dysfunctions in Senescence Cell and the Possible Interventions through Herbal Medicines

Ferro M.*, Graubard A., Escalante P., Ledezma R., Channan G., Mia N., Dotres V., Bencomo Y., Datri P.
FG Scientifica and Science Department at Nutrition Formulators Inc., Miramar, Fl, USA.

Keywords

  • Mitochondrial Biogenesis; Cell Senescence; Retrograde Signaling; Medicinal Herbs

How to Cite

Ferro M.*, Graubard A., Escalante P., Ledezma R., Channan G., Mia N., Dotres V., Bencomo Y., Datri P. (2021). Mitochondrial Metabolism, Dysfunctions in Senescence Cell and the Possible Interventions through Herbal Medicines. International Journal of Aging Research, 4(1), 78. https://doi.org/10.28933/ijoar-2021-02-1206

Abstract

The mitochondria are the cell`s powerhouse. They are considered ubiquitous organelles of all eukaryotic cells, being responsible for the cell’s life and death cycle. Through stimuli in the environment in which they live, mitochondria can modulate their own biogenesis as well as signal retrograde to the nucleus to modify the structure of their proteins. Since the mitochondrial genome contains only 37 genes, much of the encoding of its proteins depends on the nuclear genome. Thus, the communication between mitochondria and the nucleus seems to be a target of science in understanding the pathologies associated with this organelle. Some medicinal herbs have been shown to influence mitochondrial biogenesis, such as Gynostemma pentaphyllun (GP) and berberine, which increase the phosphorylation of proteins AMPactivated protein kinase (AMPK). Just as GP and berberine phosphorylate AMPK in signaling for mitochondrial biogenesis, the sesquiterpene beta-caryophyllene (BCP) demonstrated positive results in reorganizing mitochondrial transcription factors, being an agonist of the peroxisome proliferatoractivated alpha receptor (PPAR-?). Another plant derivative, the non-psychoactive cannabinoid known as cannabidiol (CBD), has been showing control in the metabolism of calcium in the mitochondrial matrix. In this review, we seek to get a closer look at the biochemical mechanisms of action of some of these plants, as well as their synergies in the results of different treatments. In the view of oriental medicines, the use of associated medicinal herbs has always been part of their treatment protocols. However, the effectiveness of these treatments in relation to plant synergy can be observed in future clinical trials for better understanding.

References

  1. FERNANDEZ-MORENO MA, BORNSTEIN B, PETIT N, GARESSE R. The pathophysiology of Mitochondrial Biogenesis: Towards Four Decades of Mitochondrial DNA Research. Molecular Genetics and Metabolism. 71, 481-495 (2000).
  2. BALABAN RS. 1990. Regulation of oxidative phosphorylation in the mammalian cell. Am J Physiol 258: C377–C389.
  3. DORN GW, VEGA RB, KELLY DP. Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev. 2015 Oct 1; 29(19): 1981–1991.
  4. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005 Jul; 85(3):1093-129.
  5. BHARGAVA P, SCHNELLMANN RG. Mitochondrial energetics in the kidney. Nat Rev Nephrol. 2017 Oct; 13(10): 629–646.
  6. POPOV L. Mitochondrial biogenesis: An update. J Cell Mol Med. 2020 May; 24(9): 4892–4899.
  7. JORNAYVAZ FR, SHULMAN GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010; 47: 10.1042/bse0470069.
  8. SIGISMUND S, CONFALONIERI S, CILIBERTO A, POLO S, SCITA G, DI FIORE PP. Endocytosis and Signaling: Cell Logistics Shape the Eukaryotic Cell Plan. Physiol Rev. 2012 Jan; 92(1): 273–366.
  9. WANG H, XU J, LAZAROVICI P, QUIRION R, ZHENG W. cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia. Front. Mol. Neurosci., 30 August 2018
  10. ALTAREJOS JY AND MONTMINY M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011 Mar; 12(3): 141–151.
  11. FERNANDEZ-MARCOS PJ AND AUWERX J. Regulation of PGC-1?, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011 Apr; 93(4): 884S–890S.
  12. LIRA VA, BENTON CR, YAN Z, AND BONEN A. PGC-1? regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab. 2010 Aug; 299(2): E145–E161.
  13. RIUS-PÉREZ S, TORRES-CUEVAS I, MILLÁN I, ORTEGA AL, AND PÉ S. PGC-1?, Inflammation, and Oxidative Stress: An Integrative View in Metabolism. Oxid Med Cell Longev. 2020; 2020: 1452696.
  14. ILANZA IR, AND NAIR KS. Regulation of Skeletal Muscle Mitochondrial Function: Genes to Proteins. Acta Physiol (Oxf). 2010 Aug; 199(4): 529–547.
  15. SCHREIBER SN, EMTER R, HOCK MB, KNUTTI D, CARDENAS J, MICHAEL PODVINEC M, et al. The estrogen-related receptor ? (ERR?) functions in PPAR? coactivator 1? (PGC-1?)-induced mitochondrial biogenesis. PNAS April 27, 2004 101 (17) 6472-6477.
  16. RAKHSHANDEHROO M, KNOCH B, MÜLLER M, AND KERSTEN S. Peroxisome Proliferator-Activated Receptor Alpha Target Genes. PPAR Res. 2010; 2010: 612089.
  17. PIANTADOSI CA, AND SULIMAN HB. Redox Regulation of Mitochondrial Biogenesis. Free Radic Biol Med. 2012 Dec 1; 53(11): 2043–2053.
  18. 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.
  19. JUNG S AND KIM K. Exercise-induced PGC-1? transcriptional factors in skeletal muscle. Integr Med Res. 2014 Dec; 3(4): 155–160.
  20. JÄGER S, HANDSCHIN C, ST.-PIERRE J, AND SPIEGELMAN BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via directphosphorylation of PGC-1?. PNAS July 17, 2007 104 (29) 12017-12022.
  21. KANG I, CHU CT, AND KAUFMAN BA. The mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms. FEBS Lett. 2018 Mar; 592(5): 793–811.
  22. KARAKAIDOS P AND RAMPIAS T. Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity. Life (Basel). 2020 Sep; 10(9): 173.
  23. TAANMAN J. The mitochondrial genome: struc-ture, transcription, translation and replication. O-chim Biophys Acta. 1999 Feb 9;1410(2):103-23.
  24. ANGELINI C, BELLO L, SPINAZZI M, AND FERRATI C. Mitochondrial disorders of the nuclear genome. Acta Myol. 2009 Jul; 28(1): 16–23.
  25. VAN DER BLIEK AM, SEDENSKY MM, AND MORGAN PG. Cell Biology of the Mitochondrion. Genetics. 2017 Nov; 207(3): 843–871.
  26. RUSECKA J, KALISZEWSKA M, BARTNIK E, AND TO?SKA K. Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA. J Appl Genet. 2018; 59(1): 43–57.
  27. FERNÁNDEZ-VIZARRA E AND ZEVIANI M. Nuclear gene mutations as the cause of mitochondrial complex III deficiency. Front Genet. 2015; 6: 134.
  28. SHARMA LK, LU J, AND BAI Y. Mitochondrial Respiratory Complex I: Structure, Function and Implication in Human Diseases. Curr Med Chem. 2009; 16(10): 1266–1277.
  29. LUO S, C. VALENCIA A, ZHANG J, LEE N, SLONE J, GUI B, WANG X, et al. Biparental Inheritance of Mitochondrial DNA in Humans. PNAS December 18, 2018 115 (51) 13039-13044.
  30. SONG W, BALLARD JWO, YI Y, AND SUTOVSKY P. Regulation of Mitochondrial Genome Inheritance by Autophagy and Ubiquitin-Proteasome System: Implications for Health, Fitness, and Fertility. Biomed Res Int. 2014; 2014: 981867.
  31. SUTOVSKY P, MORENO RD, RAMALHO-SANTOS J, DOMINKO T, SIMERLY C, SCHATTEN G. Ubiquitinated Sperm Mitochondria, Selective Proteolysis, and the Regulation of Mitochondrial Inheritance in Mammalian Embryos. Biology of Reproduction, Volume 63, Issue 2, 1 August 2000, Pages 582–590.
  32. VISSING J. Paternal comeback in mitochondrial DNA inheritance. PNAS January 29, 2019 116 (5) 1475-1476; first published January 11, 2019.
  33. TAYLOR RW AND TURNBULL DM. Mitochondrial dna mutations in human disease. Nat Rev Genet. 2005 May; 6(5): 389– 402.
  34. SALAZAR G. NADPH Oxidases and Mitochondria in Vascular Senescence. Int J Mol Sci. 2018 May; 19(5): 1327.
  35. PASSOS JF, SARETZKI G, AHMED S, NELSON G, RICHTER T, PETERS H, et al. T. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 2007;5.
  36. BONORA M, PATERGNANI S, RIMESSI A, DE MARCHI E, SUSKI JM, ANGELA BONONI A,1 et al. ATP synthesis and storage. Purinergic Signal. 2012 Sep; 8(3): 343–357.
  37. WALLACE DC, FAN W, AND PROCACCIO V. Mitochondrial Energetics and Therapeutics. Annu Rev Pathol. 2010; 5: 297– 348.
  38. KANUNGO S, MORTON J, NEELAKANTAN M, CHING K, SAEEDIAN J, AND GOLDSTEIN A. Mitochondrial disorders. Ann Transl Med. 2018 Dec; 6(24): 475.
  39. JOHANNSEN DL AND ERIC RAVUSSIN E. The role of mitochondria in health and disease. Curr Opin Pharmacol. 2009 Dec; 9(6): 780–786.
  40. FRYE RE AND ROSSIGNOL DA. Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr Res. 2011 May; 69(5 Pt 2): 41R–47R.
  41. PEI L AND WALLACE DC. Mitochondrial Etiology of Neuropsychiatric Disorders. Biol Psychiatry. 2018 May 1; 83(9): 722–730.
  42. MCINNES J. Mitochondrial-associated metabolic disorders: foundations, pathologies and recent progress. Nutr Metab (Lond). 2013; 10: 63.
  43. KHAN NA, GOVINDARAJ P, MEENA AK,* AND THANGARAJ K. Mitochondrial disorders: Challenges in diagnosis & treatment. Indian J Med Res. 2015 Jan; 141(1): 13–26.
  44. NICOLSON GL. Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements. Integr Med (Encinitas). 2014 Aug; 13(4): 35–43.
  45. MYHILL S, BOOTH NE, AND MCLAREN-HOWARD J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009; 2(1): 1–16.
  46. SCHAEFER AM, WALKER M, TURNBULL DM,A AND TAYLOR RW. Endocrine disorders in mitochondrial disease. Mol Cell Endocrinol. 2013 Oct 15; 379(1-2): 2–11.
  47. GIULIVI C, ZHANG Y, OMANSKA-KLUSEK A, ROSS-INTA C, WONG S, HERTZ-PICCIOTTO I. Mitochondrial Dysfunction in Autism. JAMA. 2010 Dec 1; 304(21): 2389–2396.
  48. GRIFFITHS KK AND LEVY RJ. Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms. Oxid Med Cell Longev. 2017; 2017: 4314025.
  49. CLAY HB, SILLIVAN S, KONRADI C. Mitochondrial Dysfunction and Pathology in Bipolar Disorder and Schizophrenia. Int J Dev Neurosci. 2011 May; 29(3): 311–324.
  50. ALLEN J, ROMAY-TALLON R, BRYMER KJ, CARUNCHO HJ, AND KALYNCHUK LE. Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression. Front Neurosci. 2018; 12: 386.
  51. WALLACE DC. Mitochondria and cancer. Nat Rev Cancer. 2012 Oct; 12(10): 685–698.
  52. GRASSO D, ZAMPIERI LX1, CAPELÔA T, VAN DE VELDE JA1 AND SONVEAUX P. Mitochondria in câncer. Cell Stress, Vol. 4, No. 6, pp. 114 – 146.
  53. SIVITZ WI AND YOREK MA. Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeu-tic Opportunities. Antioxid Redox Signal. 2010Feb 15; 12(4): 537–577.
  54. CHEN C, TURNBULL DM, AND REEVE AK. Mi-tochondrial Dysfunction in Parkinson’s Disease—Cause or Consequence? Biology (Basel). 2019 Jun; 8(2): 38.
  55. REDDY PM. Mitochondrial Dysfunction and Oxidative Stress in Asthma: Implications for Mitochondria-Targeted Antioxidant Therapeutics. Pharmaceuticals (Basel). 2011 Mar; 4(3): 429–456.
  56. CENINI G AND VOOS W. Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update. Front Pharmacol. 2019; 10: 902.
  57. WEI Y, RECTOR RS, THYFAULT JP, AND IBDAH JA. Nonalcoholic fatty liver disease and mitochondrial dysfunction. World J Gastroenterol. 2008 Jan 14; 14(2): 193–199.
  58. KOROLCHUK VI, MIWA S, CARROLL B, ZGLINICKI T. Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link? EBioMedicine 21 (2017) 7-13.
  59. VASILEIOU PVS, EVANGELOU K, VLASIS K, FILDISIS G, PANAYIOTIDIS MI, CHRONOPOULOS E, et al. Mitochondrial Homeostasis and Cellular Senescence. Cells. 2019 Jul; 8(7): 686.
  60. JENDRACH M, POHL S, VOTH M, KOWALD A, HAMMERSTEIN P, BEREITER-HAHN J. Morpho-dynamic changes of mitochondria during aging of human endothelial cells. Mech. Aging Dev. 2005;126:813–821.
  61. YOON YS, YOON DS, LIM IK, YOON SH, CHUNG HY, ROJO M, et al. Formation of elongated giant mitochondria in DFO-induced cellular senescence: Involvement of enhanced fusion process through modulation of Fis1. J. Cell. Physiol. 2006;209:468–480.
  62. GORMAN GS, CHINNERY PF, DIMAURO S, HIRANO M, KOGA Y, MCFARLAND R, et al. Thorburn D.R., Zeviani M., Turnbull D.M. Mitochondrial diseases. Nat. Rev. Dis. Primers. 2016;2:16080.
  63. TAYLOR RW AND TURNBULL DM. Mitochondr-ial DNA mutations in human disease. Nat Rev G-enet. 2005 May; 6(5): 389– 402.
  64. WHITE FA, BUNN CL. Restriction enzyme analysis of mitochondrial DNA in aging human cells. Mech Ageing Dev. 1985 May 13; 30(2):153-68.
  65. PARK SY, CHOI B, CHEON H, PAK YK, KULAWIEC M, SINGH KK, et al. Cellular aging of mitochondrial DNA-depleted cells. Biochem. Biophys. Res. Commun. 2004;325:1399–1405.
  66. BUTOW RA, AVADHANI NG. Mitochondrial signaling: the retrograde response. Mol Cell. 2004 Apr 9; 14(1):1-15.
  67. DA CUNHA FM, TORELLI NQ, AND KOWALTOWSKI AJ. Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes. Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2015, Article ID 482582, 10.
  68. CAGIN U, ENRIQUEZ JA. The complex crosstalk between mitochondria and the nucleus: What goes in between? Int J Biochem Cell Biol. 2015 Jun; 63():10-5.
  69. GUERRA F, GUARAGNELLA N, ARBINI AA, BUCCI C,GIANNATTASIO S, AND MORO L. Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer. Front Oncol. 2017; 7: 295.
  70. YANG D. KIM J. Mitochondrial Retrograde Signalling and Metabolic Alterations in the Tumour Microenvironment. Cells. 2019 Mar 22;8(3):275.
  71. JIA D, PARK JH, JUNG KH, LEVINE H, KAIPPARETTU BA. Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. Cells. 2018 Mar 13; 7(3).
  72. CHANDEL NS. Evolution of Mitochondria as Signaling Organelles. Cell Metab. 2015 Aug 4; 22(2):204-6.
  73. WENG JK, PHILIPPE RN, NOEL JP. The rise ofchemodiversity in plants. Science. 2012 Jun 29;336(6089):1667-70.
  74. LIETAVA J. Medicinal plants in a Middle Paleol-ithic grave Shanidar IV? J Ethnopharmacol. 1992 Jan; 35(3):263-6.
  75. PETROVSKA BB. Historical review of medicinal plants’ usage. Pharmacogn Rev. 2012 Jan-Jun; 6(11): 1–5.
  76. BUSSMANN RW. The Globalization of Traditional Medicine in Northern Peru: From Shamanism to Molecules. Evid Based Complement Alternat Med. 2013; 2013: 291903.
  77. BLUNT JW, CARROLL AR, COPP BR, DAVIS RA, KEYZERS RA, PRINSEP MR. Marine natural products. Nat Prod Rep. 2018 Jan 16; 35(1):8-53.
  78. Harvey AL, Clark RL, Mackay SP, Johnston BF. Current strategies for drug discovery through natural products. Expert Opin Drug Discov. 2010 Jun; 5(6):559-68.
  79. TANSAZ M, TAJADINI H. Comparison of Leiomyoma of Modern Medicine and Traditional Persian Medicine. J Evid Based Complementary Altern Med. 2016 Apr; 21(2):160-3.
  80. THOMFORD NE, AWORTWE C, DZOBO K, ADU F, CHOPERA D, WONKAM A, et al. Inhibition of CYP2B6 by Medicinal Plant Extracts: Implication for Use of Efavirenz and Nevirapine-Based Highly Active Anti-Retroviral Therapy (HAART) in Resource-Limited Settings. Molecules. 2016 Feb 16; 21(2).
  81. THOMFORD NE, DZOBO K, CHOPERA D, WONKAM A, SKELTON M, BLACKHURST D, CHIRIKURE S, DANDARA C. Pharmacogenomics Implications of Using Herbal Medicinal Plants on African Populations in Health Transition. Pharmaceuticals (Basel). 2015 Sep 21; 8(3):637-63.
  82. RUHSAM M, HOLLINGSWORTH PM. Authentication of Eleutherococcus and Rhodiola herbal supplement products in the United Kingdom. J Pharm Biomed Anal. 2018 Feb 5; 149():403-409.
  83. SOFOWORA A, OGUNBODEDE E, AND ONAYADE A. The Role and Place of Medicinal Plants in the Strategies for Disease Prevention. Afr J Tradit Complement Altern Med. 2013; 10(5): 210–229.
  84. GERTSCH J, LEONTI M, RADUNER S, RACZ I, CHEN J, XIE X et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. 2008 Jul 1; 105(26): 9099–9104.
  85. LEGAULT J, PICHETTE A. Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol. 2007 Dec;59(12):1643-7.
  86. HASHIESH HM, MEERAN MFN, SHARMA C, SADEK B, AL KAABI J AND OJHA SK. Therapeutic Potential of ?-Caryophyllene: A Dietary Cannabinoid in Diabetes and Associated Complications. Nutrients 2020, 12(10), 2963
  87. YOUSSEF DA, EL-FAYOUMI HM, MAHMOUD MF. Beta-caryophyllene protects against diet-induced dyslipidemia and vascular inflammation in rats: Involvement of CB2 and PPAR-? receptors. Chem Biol Interact. 2019 Jan 5;297:16-24.
  88. CHEN L, LI L, CHEN J, LI L, ZHENG Z, REN J, AND QIU Y. Oleoylethanolamide, an endogenous PPAR-? ligand, attenuates liver fibrosis targeting hepatic stellate cells. Oncotarget. 2015 Dec 15; 6(40): 42530–42540.
  89. OJHA S, JAVED H, AZIMULLAH S, HAQUE ME. ?-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol Cell Biochem. 2016 Jul;418(1-2):59-70.
  90. KLAUDYNA FIDYT, ANNA FIEDOROWICZ, LEON STRZ?DA?A, AND ANTONI SZUMNY. ??caryophyllene and ??caryophyllene oxide—natural compounds of anticancer and analgesic properties. Cancer Med. 2016 Oct; 5(10): 3007–3017.
  91. ZHENG, GQ, KENNEY PM, AND LAM LK. Sesquiterpenes from clove (Eugenia caryophyllata) as potential anticarcinogenic agents. J. Nat. Prod. 1992. 55:999–1003.
  92. PARK K, NAM D, YUN H, LEE S, JANG H, SETHI G, et al. ?-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett. 2011 Dec 22;312(2):178-88.
  93. PARK MH and HONG JT. Roles of NF-?B in Cancer and Inflammatory Diseases and Their Therapeutic Approaches. Cells. 2016 Jun; 5(2): 15.
  94. KIM C, CHO SK, KIM K, NAM D, CHUNG W, JANG H, et al. ?-Caryophyllene oxide potentiates TNF?-induced apoptosis and inhibits invasion through down-modulation of NF-?B-regulated gene products. Apoptosis. 2014 Apr;19(4):708-18.
  95. LANG SJ, SCHMIECH M, HAFNER S, PAETZ C, STEINBORN C , HUBER R, et al. Antitumor activity of an Artemisia annua herbal preparation and identification of active ingredients. Phytomedicine. 2019 Sep; 62:152962.
  96. KONSTAT-KORZENNY E, ASCENCIO-ARAGÓN JA, NIEZEN-LUGO S, ROSALINO VÁZQUEZ-LÓPEZ R. Artemisinin and Its Synthetic Derivatives as a Possible Therapy for Cancer. Med Sci (Basel). 2018 Feb 27;6(1):19.
  97. CRESPO-ORTIZ MP, WEI MQ. Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. J Biomed Biotechnol. 2012; 2012:247597.
  98. DU J, ZHANG H · MA Z, JI K. Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother Pharmacol (2010) 65:895–902.
  99. O’NEILL PM, BARTON VE, AND STEPHEN A. WARD SA. The Molecular Mechanism of Action of Artemisinin—The Debate Continues. Molecules. 2010 Mar; 15(3): 1705–1721.
  100. CHEN G, BENTHANI FA, WU J, LIANG D, BIAN Z AND JIANG X. Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death & Differentiation volume 27, pages242–254(2020)
  101. CRESPO-ORTIZ MP AND WE MQ. Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug. J Biomed Biotechnol. 2012;2012:247597.
  102. PAUL BT, MANZ DH, TORTI FM, AND TORTI SV. Mitochondria and Iron: Current Questions. Expert Rev Hematol. 2017 Jan; 10(1): 65–79.
  103. HOROWITZ MP AND GREENAMYRE JT. Mitochondrial Iron Metabolism and Its Role in Neurodegeneration. J Alzheimers Dis. 2010; 20(Suppl 2): S551–S568.
  104. WANG J, HUANG L, LI J, FAN Q, LONG Y, LI Y, AND ZHOU B. Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation. PLoS One. 2010; 5(3): e9582.
  105. KRISHNA S, BUSTAMANTE L, HAYNES RK, STAINES HM. Artemisinins: their growing importance in medicine. Trends Pharmacol Sci. 2008 Oct;29(10):520-7.
  106. LI BQ, WEINA P AND HICKMAN M. The Use of Artemisinin Compounds as Angiogenesis Inhibitors to Treat Cancer. Intechopen February 2013.
  107. PIOTR WÓJCIK P, NEVEN ŽARKOVI? N, AGNIESZKA G?GOTEK A, AND EL?BIETA SKRZYDLEWSKA E. Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis. Biomolecules. 2020 Mar; 10(3): 402.
  108. RIMMERMAN N, BEN-HAI D, PORAT Z, JUKNAT A, KOZELA E,1 DANIELS MP, et al. Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death. Cell Death Dis. 2013 Dec; 4(12): e949.
  109. OLIVAS-AGUIRRE M, TORRES-LÓPEZ L, VALLE-REYES JS, HERNÁNDEZ-CRUZ A, POTTOSIN I AND DOBROVINSKAYA O. Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia. Cell Death & Disease volume 10, Article number: 779 (2019).
  110. RYAN, D, DRYSDALE A.J, LAFOURCADE C, PERTWEE RG. AND PLATT B. Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J. Neurosci. 29, 2053–2063 (2009).
  111. ORRENIUS S, GOGVADZE V. & ZHIVOTOVSKY B. Calcium and mitochondria in the regulation of cell death. Biochem. Biophys. Res. Commun. 460, 72–81 (2015).
  112. GIORGIO V, GUO L, BASSOT C, PETRONILLI V AND BERNARDI P. Calcium and regulation of the mitochondrial permeability transition. Cell Calcium 70, 56–63 (2018). Return to ref 20 in article.
  113. GIACOMELLO M. AND PELLEGRINI, L. The coming of age of the mitochondria-ER contact: a matter of thickness. Cell Death Differ. 23, 1417–1427 (2016).
  114. LOWIN T, TINGTING R, ZURMAHR J, CLASSEN T, SCHNEIDER M, AND PONGRATZ G. Cannabidiol (CBD): a killer for inflammatory rheumatoid arthritis synovial fibroblasts. Cell Death Dis. 2020 Aug; 11(8): 714.
  115. VALERO T. Mitochondrial biogenesis: pharmacological approaches. Curr Pharm Des. 2014;20(35):5507-9.
  116. TEODORO JS, DUARTE FV, GOMES AP, VARELA AT, PEIXOTO FM, ROLO AP, et al. Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: a possible role for SirT3 activation. Mitochondrion. 2013 Nov;13(6):637-46.
  117. NGUYEN PH, GAUHAR R, HWANG SL, DAO TT, PARK DC, KIM JE, et al. New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum. Bioorg Med Chem. 2011 Nov 1;19(21):6254-60.
  118. LEE YS, KIM WS, KIM KH, YOON MJ, CHO HJ, SHEN Y, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006 Aug;55(8):2256-64.
  119. XIA X, YAN J, SHEN Y, TANG K, YIN J, ZHANG Y, et al. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One. 2011 Feb 3;6(2):e16556.
  120. GOMES AP, DUARTE FV, NUNES P, HUBBARD BP, TEODORO JS, VARELA AT, ET AL. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta. 2012 Feb;1822(2):185-95.
  121. CANTÓ C, GERHART-HINES Z, FEIGE JN, LAGOUGE M, NORIEGA L, MILNE JC. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009 Apr 23;458(7241):1056-60.
  122. LAN F, CACICEDO JM, RUDERMAN N, IDO Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008 Oct 10;283(41):27628-35.
  123. LEE HS, LIM S, JUNG JI, KIM SM, LEE JK, KIM YH, et al. Gynostemma Pentaphyllum Extract Ameliorates High-Fat DietInduced Obesity in C57BL/6N Mice by Upregulating SIRT1. Nutrients 2019, 11(10), 2475.
  124. GAUHAR R, HWANG S, JEONG S, KIM J, SONG H, PARK DC, et al. Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase. Biotechnology Letters. May 2012; 34(9):1607-16.
  125. SHAITO A, THUAN DTB, PHU HT, NGUYEN THD, HASAN H, HALABI S, et al. Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety. Front Pharmacol. 2020; 11: 422.
  126. LOKMAN EF, GU HF, MOHAMUD WNW, AND CLAES-GÖRAN ÖSTENSON C. Evaluation of Antidiabetic Effects of the Traditional Medicinal Plant Gynostemma pentaphyllum and the Possible Mechanisms of Insulin Release. Evid Based Complement Alternat Med. 2015; 2015: 120572.
  127. YU J AND AUWERX J. Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation. Pharmacol Res. 2010 Jul; 62(1): 35–41.
  128. HWANG J, YAO H, CAITO S, SUNDAR IK, AND RAHMAN I. Redox regulation of sirt1 in inflammation and cellular senescence. Free Radic Biol Med. 2013 Aug; 0: 95–110.
  129. BORRA MT, SMITH BC, DENU JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005 Apr 29;280(17):17187-95.
  130. CHAO S, CHEN Y, HUANG K, KUO K, YANG T, HUANG K, et al. Induction of sirtuin-1 signaling by resveratrol induces human chondrosarcoma cell apoptosis and exhibits antitumor activity. Sci Rep. 2017; 7: 3180.
  131. BUHRMANN C, SHAYAN P, POPPER B, GOEL A, AND SHAKIBAEI M. Sirt1 Is Required for Resveratrol-Mediated Chemopreventive Effects in Colorectal Cancer Cells. Nutrients. 2016 Mar; 8(3): 145.
  132. FRAZZI R, VALLI R, TAMAGNINI I, CASALI B, LATRUFFE N, MERLI F. Resveratrol-mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation. Int J Cancer. 2013 Mar 1; 132(5):1013-21.
  133. ASHRAFIZADEH M, JAVANMARDI S, MORADI-OZARLOU M, MOHAMMADINEJAD R, FARKHONDEH T, SAMARGHANDIAN S, SAMARGHANDIAN S, et al. Natural products and phytochemical nanoformulations targeting mitochondria in oncotherapy: an updated review on resveratrol. Biosci Rep. 2020 Apr 30; 40(4): BSR20200257.
  134. ZHOU J, ZHOU M, YANG FF, LIU CY, PAN RL, CHANG Q, et al. Involvement of the inhibition of intestinal glucuronidation in enhancing the oral bioavailability of resveratrol by labrasol containing nanoemulsions. Mol Pharm. 2015 Apr 6; 12(4):1084-95.
  135. WARBURG O. On the origin of cancer cells. Science. 1956 Feb 24; 123(3191):309-14.
  136. KUECK A, OPIPARI AW JR, GRIFFITH KA, TAN L, CHOI M, HUANG J, et al. Resveratrol inhibits glucose metabolism in human ovarian cancer cells. Gynecol Oncol. 2007 Dec; 107(3):450-7.
  137. BLANQUER-ROSSELLÓ MD, HERNÁNDEZ-LÓPEZ R, ROCA P, OLIVER J, VALLE A. Resveratrol induces mitochondrial respiration and apoptosis in SW620 colon cancer cells. Biochim Biophys Acta Gen Subj. 2017 Feb; 1861(2):431-440.
  138. DOMINY JE AND PUIGSERVER P. Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins. Cold Spring Harb Perspect Biol. 2013 Jul; 5(7): a015008.
  139. NATHAN L. PRICE NL, ANA P. GOMES AP, ALVIN J.Y. LING AJY, FILIPE V. DUARTE FV, ALEJANDRO MARTIN-MONTALVO A, BRIAN J. NORTH BJ, 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.
  140. DACHE ZA, OTANDAULT A, TANOS R, PASTOR B, MEDDEB R, SANCHEZ C, et al. Blood contains circulating cell-free respiratory competent mitochondria. FASEB J. 2020 Mar;34(3):3616-3630.
  141. THIERRY AR, EL MESSAOUDI S, GAHAN PB, ANKER P, AND STROUN M. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev. 2016; 35(3): 347–376.
  142. TORRALBA D, BAIXAULI F, AND SÁNCHEZ-MADRID F. Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer. Front Cell Dev Biol. 2016; 4: 107.
  143. RODRIGUEZ A, NAKHLE J, GRIESSINGER E, VIGNAIS M. Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury. Cell cycle (Georgetown, Tex.) 17(6):1-25. March 2018.
  144. PATEL D, RORBACH J, DOWNES K, SZUKSZTO MJ, PEKALSKI ML AND MINCZUK M. Macropinocytic entry of isolated mitochondria in epidermal growth factor-activated human osteosarcoma cells. Scientific Reports volume 7, Article number: 12886 (2017).
  145. WANG J, LI H, YAO Y, ZHAO T, CHEN Y, SHEN Y, et al. Stem cell-derived mitochondria transplantation: a novel strategy and the challenges for the treatment of tissue injury. Stem Cell Research & Therapy volume 9, Article number: 106 (2018).
  146. RIBAS V, GARCÍA-RUIZ C AND FERNÁNDEZ-CHECA JC. Glutathione and mitochondria. Front Pharmacol. 2014 Jul 1;5:151.
  147. WANG H, JIANG H, CORBET C, DE MEY S, LAW K, GEVAERT T, et al. Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems. Cancer Lett. 2019 May 28;450:42-52.
  148. MA Q. Role of Nrf2 in Oxidative Stress and Toxicity. Annu Rev Pharmacol Toxicol. 2013; 53: 401–426.
  149. TU W, WANG H, LI S, LIU Q, AND SHA H. The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases. Aging Dis. 2019 Jun; 10(3): 637–651.
  150. CHIAN S, THAPA R, CHI Z, WANG XJ, TANG X. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo.