Metformin

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Metformin

Description

Metformin is mainly known as an important antidiabetic drug which is effective, however, in a wide spectrum of degenerative diseases. It is an inhibitor of Complex I.


Reference: Brunmair 2004 Diabetes

Metformin and mitObesity

Work in progress by Gnaiger E 2020-02-10 linked to a preprint in preparation on BME and mitObesity.

References: Metformin

 YearReferenceOrganismTissue;cell
Machado 2019 MitoFit Preprint Arch EA2019-06-17Machado Ivo F, Teodoro JS, Palmeira CM, Rolo AP (2019) Interplay between metformin and miR-378a-3p in cells under hyperglycaemia. MitoFit Preprint Arch doi:10.26124/mitofit:ea19.MiPSchool.0008.
Kenny 2019 Circ Res2019Kenny HC, Abel ED (2019) Heart failure in Type 2 Diabetes Mellitus. Circ Res 124:121–41.HumanHeart
Teh 2019 Mol Cancer Ther2019Teh JT, Zhu WL, Newgard CB, Casey PJ, Wang M (2019) Respiratory capacity and reserve predict cell sensitivity to mitochondria inhibitors: mechanism-based markers to identify metformin-responsive cancers. Mol Cancer Ther 18:693-705.Human
Mouse
Other cell lines
Ruegsegger 2019 JCI Insight2019Ruegsegger GN, Vanderboom PM, Dasari S, Klaus KA, Kabiraj P, McCarthy CB, Lucchinetti CF, Nair KS (2019) Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain. JCI Insight 4:130681.MouseNervous system
Gabandé-Rodríguez 2019 Cells2019Gabandé-Rodríguez E, M Gómez de Las Heras M, Mittelbrunn M (2019) Control of inflammation by calorie restriction mimetics: on the crossroad of autophagy and mitochondria. Cells 2019;9:E82.
Rivas 2018 Am J Physiol Endocrinol Metab2018Rivas E, Herndon DN, Porter C, Meyer W, Suman OE. (2018) Short-term metformin and exercise training effects on strength, aerobic capacity, glycemic control, and mitochondrial function in children with burn injury.. Am J Physiol Endocrinol Metab. 314(3):E232-E240.HumanSkeletal muscle
Zhou 2018 Cell Death Dis2018Zhou C, Sun H, Zheng C, Gao J, Fu Q, Hu N, Shao X, Zhou Y, Xiong J, Nie K, Zhou H, Shen L, Fang H, Lyu J (2018) Oncogenic HSP60 regulates mitochondrial oxidative phosphorylation to support Erk1/2 activation during pancreatic cancer cell growth. Cell Death Dis 9:161.HumanIslet cell;pancreas;thymus
Other cell lines
Arnoux 2018 Elife2018Arnoux I, Willam M, Griesche N, Krummeich J, Watari H, Offermann N, Weber S, Narayan Dey P, Chen C, Monteiro O, Buettner S, Meyer K, Bano D, Radyushkin K, Langston R, Lambert JJ, Wanker E, Methner A, Krauss S, Schweiger S, Stroh A (2018) Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease. Elife 7:e38744.MouseNervous system
Piel 2018 Intensive Care Med Exp2018Piel S, Ehinger JK, Chamkha I, Frostner EÅ, Sjövall F, Elmér E, Hansson MJ (2018) Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production. Intensive Care Med Exp 6:22.HumanPlatelet
Blood cells
Konopka 2018 Aging Cell2018Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, Musci RV, Safairad OD, Linden MA, Biela LM, Bailey SM, Hamilton KL, Miller BF (2018) Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell 18:e12880.HumanSkeletal muscle
Tai 2018 Acta Pharm Sin B2018Tai Y, Li L, Peng X, Zhu J, Mao X, Qin N, Ma M, Huo R, Bai Y, Dong D (2018) Mitochondrial uncoupler BAM15 inhibits artery constriction and potently activates AMPK in vascular smooth muscle cells. Acta Pharm Sin B 8:909-18.MouseEndothelial;epithelial;mesothelial cell
Machado-Neto 2018 Cell Death Dis2018Machado-Neto JA, Fenerich BA, Scopim-Ribeiro R, Eide CA, Coelho-Silva JL, Dechandt CRP, Fernandes JC, Rodrigues Alves APN, Scheucher PS, Simões BP, Alberici LC, de Figueiredo Pontes LL, Tognon CE, Druker BJ, Rego EM, Traina F (2018) Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms. Cell Death Dis 9:311.Human
Mouse
Other cell lines
Wilmanns 2018 Mol Metab2018Wilmanns JC, Pandey R, Hon O, Chandran A, Schilling JM, Forte E, Wu Q, Cagnone G, Bais P, Philip V, Coleman D, Kocalis H, Archer SK, Pearson JT, Ramialison M, Heineke J, Patel HH, Rosenthal NA, Furtado MB, Costa MW (2018) Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease. Mol Metab 20:102-14.MouseHeart
Christensen 2018 Diabetes Metab Res Rev2018Christensen M, Schiffer TA, Gustafsson H, Krag SP, Nørregaard R, Palm F (2018) Metformin attenuates renal medullary hypoxia in diabetic nephropathy through uncoupling protein-2 inhibition. Diabetes Metab Res Rev 21:e3091.RatKidney
Schommers 2017 Mol Metab2017Schommers P, Thurau A, Bultmann-Mellin I, Guschlbauer M, Klatt AR, Rozman J, Klingenspor M, de Angelis MH, Alber J, Gründemann D, Sterner-Kock A, Wiesner RJ (2017) Metformin causes a futile intestinal-hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state. Mol Metab 6:737-47.Mouse
Pecinova 2017 Oxid Med Cell Longev2017Pecinova A, Drahota Z, Kovalcikova J, Kovarova N, Pecina P, Alan L, Zima M, Houstek J, Mracek T (2017) Pleiotropic effects of biguanides on mitochondrial reactive oxygen species production. Oxid Med Cell Longev 7038603.RatFat
Wetzel 2017 Thesis2017Wetzel MD (2017) Mechanism of metformin action in dermal fibroblasts. PhD Thesis 125.HumanFibroblast
Alcocer-Gomez 2016 Biochim Biophys Acta2016Alcocer-Gómez E, Garrido-Maraver J, Bullón P, Marín-Aguilar F, Cotán D, Carrión AM, Alvarez-Suarez JM, Giampieri F, Sánchez-Alcazar JA, Battino M, Cordero MD (2016) Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patient. Biochim Biophys Acta 1852:1257-67.MouseFibroblast
Villani 2016 Mol Metab2016Villani LA, Smith BK, Marcinko K, Ford RJ, Broadfield LA, Green AE, Houde VP, Muti P, Tsakiridis T, Steinberg GR (2016) The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. Mol Metab 5:1048-56.HumanGenital
Cahova 2016 Am J Physiol Gastrointest Liver Physiol2016Cahova M, Palenickova E, Dankova H, Sticova E, Burian M, Drahota Z, Cervinkova Z, Kucera O, Gladkova C, Stopka P, Krizova J, Papackova Z, Oliyarnyk O, Kazdova L (2016) Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol 309:G100-11.RatLiver
Cheng 2016 Nat Immunol2016Cheng SC, Scicluna BP, Arts RJ, Gresnigt MS, Lachmandas E, Giamarellos-Bourboulis EJ, Kox M, Manjeri GR, Wagenaars JA, Cremer OL, Leentjens J, van der Meer AJ, van de Veerdonk FL, Bonten MJ, Schultz MJ, Willems PH, Pickkers P, Joosten LA, van der Poll T, Netea MG (2016) Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol 17:406-13.HumanBlood cells
Lymphocyte
Timmers 2016 Diabetes Care2016Timmers S, de Ligt M, Phielix E, van de Weijer T, Hansen J, Moonen-Kornips E, Schaart G, Kunz I, Hesselink MK, Schrauwen-Hinderling VB, Schrauwen P (2016) Resveratrol as add-on therapy in subjects with well-controlled type 2 diabetes: a randomized controlled trial. Diabetes Care 39:2211-17.HumanSkeletal muscle
Rajh 2016 PLOS ONE2016Rajh M, Dolinar K, Miš K, Pavlin M, Pirkmajer (2016) Medium renewal blocks antiproliferative effects of metformin in cultured MDA-MB-231 breast cancer cells. PLOS ONE 11:e0154747.HumanGenital
Other cell lines
Cheng 2014 Science2014Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JH, Rao NA, Aghajanirefah A, Manjeri GR6, Li Y, Ifrim DC, Arts RJ, van der Meer BM, Deen PM, Logie C, O'Neill LA, Willems P, van de Veerdonk FL, van der Meer JW, Ng A, Joosten LA, Wijmenga C, Stunnenberg HG, Xavier RJ, Netea MG (2014) mTOR- and HIF-1 α–mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345:1250684.HumanBlood cells
Other cell lines
Piel 2014 Acta Physiol (Oxf)2014Piel S, Ehinger JK, Elmér E, Hansson Magnus J (2014) Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta Physiol (Oxf) 213:171-80.HumanBlood cells
Other cell lines
Platelet
Drahota 2014 Physiol Res2014Drahota Z, Palenickova E, Endlicher R, Milerova M, Brejchova J, Vosahlikova M, Svoboda P, Kazdova L, Kalous M, Cervinkova Z, Cahova M (2014) Biguanides inhibit complex I, II and IV of rat liver mitochondria and modify their functional properties. Physiol Res 63:1-11.RatLiver
Svendsen 2014 Thesis2014Svendsen PF (2014) Metabolic aspects of polycystic ovary syndrome and obesity. Thesis Copenhagen University Hospital:38 pp.Human
Wessels 2014 PLoS One2014Wessels B, Ciapaite J, van den Broek NMA, Nicolay K, Prompers JJ (2014) Metformin Impairs Mitochondrial Function in Skeletal Muscle of Both Lean and Diabetic Rats in a Dose-Dependent Manner. PLoS One 9:e100525.RatSkeletal muscle
Kristensen 2013 PLoS One2013Kristensen JM, Larsen S, Helge JW, Dela F, Wojtaszewski JFP (2013) Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice. PLoS One 8:e53533.MouseSkeletal muscle
Palenickova 2011 Physiol Res2011Palenickova E, Cahova M, Drahota Z, Kazdova L, Kalous M (2011) Inhibitory effect of metformin on oxidation of NADH-dependent substrates in rat liver homogenate. Physiol Res 60:835-9.RatLiver
Benes 2011 Clin Sci (Lond)2011Benes J, Kazdova L, Drahota Z, Houstek J, Medrikova D, Kopecky J, Kovarova N, Vrbacky M, Sedmera D, Strnad H, Kolar M, Petrak J, Benada O, Skaroupkova P, Cervenka L, Melenovsky V (2011) Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. Clin Sci (Lond) 121:29-41.RatHeart
Kane 2010 Free Radic Biol Med2010Kane DA, Anderson EJ, Price III JW, Woodlief TL, Lin C-T, Bikman BT, Cortright RN, Neufer PD (2010) Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med 49:1082–7.RatSkeletal muscle
Canto 2009 Nature2009Cantó AC, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458:1056-60.MouseSkeletal muscle
Morota 2009 Exp Neurol2009Morota S, Månsson R, Hansson Magnus J, Kasuya K, Shimazu M, Hasegawa E, Yanagi S, Omi A, Uchino H, Elmér E (2009) Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders-specificity vs. toxicity. Exp Neurol 218:353-62.HumanLiver
Brunmair 2004 Diabetes2004Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, Roden M, Gnaiger E, Nohl H, Waldhäusl W, Fürnsinn C (2004) Thiazolidinediones, like metformin, inhibit respiratory Complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53:1052-9.RatSkeletal muscle
Liver
 YearReferenceOrganismTissue;cell
Pavlovic 2019 MiP20192019
Barbara Cannon
Effects of therapeutic metformin concentration on mitochondria in muscle cells.
MouseSkeletal muscle
Avram 2019 MiP20192019
Vlad Avram
Cell-permeable succinate bypasses statin-induced decrease in mitochondrial ATP-generating respiration in human platelets.
HumanPlatelet
Jeremic 2019 MiP20192019
Marija Jeremic
Neurotoxic effect of extracellular alpha-synuclein can be alleviated by AMPK and autophagy.
HumanNeuroblastoma
Avram 2018 MiP20182018
MiPsociety
Cell-permeable succinate bypasses statin-induced mitochondrial complex I inhibition in human platelets. Avram_Presentation
HumanPlatelet
Siewiera 2018 MiPschool Tromso E22018
Karolina Siewiera
Effect of metformin treatment on blood platelet bioenergetics and platelet function in STZ-diabetic and non-diabetic rats.
RatPlatelet
Konopka 2018 FASEB J2018Konopka AR, Castor WM, Reid J, Schoenberg H, Laurin J, Wolff C, Hamilton K, Miller B (2018) Metformin blunts exercise-induced improvements in skeletal muscle mitochondrial respiration independent of changes in mitochondrial biogenesis. FASEB J.HumanSkeletal muscle
Brazdova 2017 MiP20172017
Brazdova Andrea
Pleiotropic effects of biguanides on mitochondrial reactive oxygen species production.
Fat
Kopitar-Jerala 2017 Abstract MITOEAGLE Barcelona2017
COST Action MITOEAGLE
Pecinova 2017 MiP20172017
Pecinova A
Targeting tumor cell proliferation by inhibition of mitochondrial metabolic pathways.
Siewiera 2017 Abstract MITOEAGLE Barcelona2017
COST Action MITOEAGLE
The effect of metformin on blood platelet bioenergetics and platelet function.
HumanBlood cells
Platelet
Forbes-Hernandez 2017 MiPschool Obergurgl2017
COST Action MitoEAGLE
The reduction of mitochondrial functionality by a strawberry extract: a mechanism that contributes to its lipid-lowering effect?
HumanLiver
Scatena 2017 MITOEAGLE Obergurgl2017
Roberto Scatena
Cancer stem cell differentiation induced by PPAR ligands. Which role for an inhibition of mitochondrial respiratory chain?
HumanLiver
Labieniec-Watala 2017 MiP20172017
Magda Labieniec-Watala
Lack of the effect of low metformin concentrations on the response of breast cancer cell mitochondria to radiotherapy under conditions of the in vitro experimental hyperglycemia. Labieniec-Watala_Presentation
HumanGenital
Scatena 2017 Abstract MITOEAGLE Barcelona2017
COST Action MITOEAGLE
Mitochondria and cancer stem cells in hepatocarcinoma. An illustrative example of a tangled methodological approach.
Liver
Murphy 2016 Abstract FASEB J2016Metformin limits loss of mitochondrial respiration seen with doxorubicin treatment without affecting muscle function.MouseSkeletal muscle
Ehinger 2015 Abstract MiPschool London 20152015Cell-permeable mitochondrial complex II substrates – a new compound class for treatment of complex I-linked mitochondrial disease.HumanHeart
Blood cells
Fibroblast
Jana Prado 2014 Abstract MiP20142014Defining the role of mitochondrial electron transfer Complex I on the modulation of Ca2+ homeostasis: effects of metformin on cancer cell metabolism. Mitochondr Physiol Network 19.13.
  1. Dantas-Ferreira RF, Raingard H, Dumont S, Schuster-Klein C, Guardiola-Lemaitre B, Pevet P, Challet E (2018) Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high-fat-fed rats. Endocrinol Diabetes Metab 1:e00039. - https://www.ncbi.nlm.nih.gov/pubmed/30815567
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  6. Kothari S, Dhami-Shah H, Shah SR (2019) Antidiabetic drugs and statins in nonalcoholic fatty liver disease. J Clin Exp Hepatol 9:723-30. - https://www.ncbi.nlm.nih.gov/pubmed/31889754
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  8. Crocker CL, Baumgarner BL, Kinsey ST (2019) β-guanidinopropionic acid and metformin differentially impact autophagy, mitochondria and cellular morphology in developing C2C12 muscle cells. J Muscle Res Cell Motil. 2019 Dec 13. doi: 10.1007/s10974-019-09568-0. - https://www.ncbi.nlm.nih.gov/pubmed/31836952
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  18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654524/
  19. https://www.ncbi.nlm.nih.gov/pubmed/30151735
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MitoPedia: mitObesity drugs

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TermAbbreviationDescription
CurcuminCurcumin has been shown to possess significant anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-mutagenic, anti-coagulant and anti-infective effects. The protective effects of curcumin on rat heart mitochondrial injuries induced by in vitro anoxia–reoxygenation were evaluated by Xu et al 2013. It was found that curcumin added before anoxia or immediately prior to reoxygenation exhibited remarkable protective effects against anoxia–reoxygenation induced oxidative damage to mitochondria.
ElamipretideBendaviaBendavia (Elamipretide) was developed as a mitochondria-targeted drug against degenerative diseases, including cardiac ischemia-reperfusion injury. Clinical trials showed variable results. It is a cationic tetrapeptide which readily passes cell membranes, associates with cardiolipin in the mitochondrial inner membrane. Supercomplex-associated CIV activity significantly improved in response to elamipretide treatment in the failing human heart.
FlavonoidsFlavonoids are a group of bioactive polyphenols with potential antioxidant and anti-inflammatory effects, abundant in fruits and vegetables, and in some medicinal herbs. Flavonoids are synthesized in plants from phenylalanine. Dietary intake of flavonoids as nutraceuticals is discussed for targeting T2D and other degenerative diseases.
MelatoninaMTMelatonin (N-acetyl-5-methoxytryptamine, aMT) is a highly conserved molecule present in unicellular to vertebrate organisms. Melatonin is synthesized from tryptophan in the pinealocytes by the pineal gland and also is produced in other organs, tissues and fluids (extrapineal melatonin). Melatonin has lipophilic and hydrophilic nature which allows it to cross biological membranes. Therefore, melatonin is present in all subcellular compartments predominantly in the nucleus and mitochondria. Melatonin has pleiotropic functions with powerful antioxidant, anti-inflammatory and oncostatic effects with a wide spectrum of action particularly at the level of mitochondria. » MiPNet article
MetforminMetformin is mainly known as an important antidiabetic drug which is effective, however, in a wide spectrum of degenerative diseases. It is an inhibitor of Complex I.
RapamycinRapamycin is an inhibitor of the mammalian/mechanistic target of rapamycin, complex 1 (mTORC1). Rapamycin induces autophagy and dyscouples mitochondrial respiration. Rapamycin delays senescence in human cells, and extends lifespan in mice without detrimental effects on mitochondrial fitness in skeletal muscle.
ResveratrolResveratrol is a natural bioactive phenol prouced by several plants with antioxidant and anti-inflammatory effects. Dietary intake as nutraceutical is discussed for targeting mitochondria with a wide spectrum of action in degenerative diseases.
SpermidineSpermidine is a polycationic bioactive polyamine mainly found in wheat germ, soybean and various vegetables, involved in the regulation of mitophagy, cell growth and cell death. Like other caloric restriction mimetics, spermidine is effective in cardioprotection, neuroprotection and anticancer immunosuppression by preserving mitochondrial function and control of autophagy.
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