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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 and glycerophosphate dehydrogenase complex.

Reference: Brunmair 2004 Diabetes

Metformin and mitObesity

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

References: Metformin

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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
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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
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
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
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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
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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
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
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.
Jeremic 2019 MiP20192019
Marija Jeremic
Neurotoxic effect of extracellular alpha-synuclein can be alleviated by AMPK and autophagy.
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
Avram 2018 MiP20182018
Cell-permeable succinate bypasses statin-induced mitochondrial complex I inhibition in human platelets. Avram_Presentation
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.
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
Scatena 2017 Abstract MITOEAGLE Barcelona2017
Mitochondria and cancer stem cells in hepatocarcinoma. An illustrative example of a tangled methodological approach.
Brazdova 2017 MiP20172017
Brazdova Andrea
Pleiotropic effects of biguanides on mitochondrial reactive oxygen species production.
Kopitar-Jerala 2017 Abstract MITOEAGLE Barcelona2017
Pecinova 2017 MiP20172017
Pecinova A
Targeting tumor cell proliferation by inhibition of mitochondrial metabolic pathways.
Siewiera 2017 Abstract MITOEAGLE Barcelona2017
The effect of metformin on blood platelet bioenergetics and platelet function.
HumanBlood cells
Forbes-Hernandez 2017 MiPschool Obergurgl2017
The reduction of mitochondrial functionality by a strawberry extract: a mechanism that contributes to its lipid-lowering effect?
Scatena 2017 MITOEAGLE Obergurgl2017
Roberto Scatena
Cancer stem cell differentiation induced by PPAR ligands. Which role for an inhibition of mitochondrial respiratory chain?
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
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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. -
  2. Alshahrani A, AlDubayee M, Zahra M, Alsebayel FM, Alammari N, Alsudairy F, Almajed M, Aljada A (2019) Differential expression of human N-alpha-acetyltransferase 40 (hNAA40), nicotinamide phosphoribosyltransferase (NAMPT) and Sirtuin-1 (SIRT-1) pathway in obesity and T2DM: modulation by metformin and macronutrient intake. Diabetes Metab Syndr Obes 12:2765-74. -
  3. Sanches-Silva A, Testai L, Nabavi SF, Battino M, Devi KP, Tejada S, Sureda A, Xu S, Yousefi B, Majidinia M, Russo GL, Efferth T, Nabavi SM, Farzaei MH (2020) Therapeutic potential of polyphenols in cardiovascular diseases: regulation of mTOR signaling pathway. Pharmacol Res 2020 Jan 2:104626. -
  4. Srivastava SB (2019) Is there a prescription to treat pediatric obesity? Am J Lifestyle Med 14:36-9. -
  5. McCrimmon RJ, Catarig AM, Frias JP, Lausvig NL, le Roux CW, Thielke D, Lingvay I (2020) Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial. Diabetologia 2020 Jan 2. doi: 10.1007/s00125-019-05065-8. -
  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. -
  7. Hiluy JC, Nazar BP, Gonçalves WS, Coutinho W, Appolinario JC (2019) Effectiveness of pharmacologic interventions in the management of weight gain in patients with severe mental illness: a systematic review and meta-analysis. Prim Care Companion CNS Disord 21 pii: 19r02483. -
  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. -
  9. Guo H, Kong W, Zhang L, Han J, Clark LH, Yin Y, Fang Z, Sun W, Wang J, Gilliam TP, Lee D, Makowski L, Zhou C, Bae-Jump VL (2019) Reversal of obesity-driven aggressiveness of endometrial cancer by metformin. Am J Cancer Res 9:2170-93. -
  10. Wang Y, An H, Liu T, Qin C, Sesaki H, Guo S, Radovick S, Hussain M, Maheshwari A, Wondisford FE, O'Rourke B, He L (2019) Metformin improves mitochondrial respiratory activity through activation of AMPK. Cell Rep 29:1511-23.e5. -
  11. MacNeil LT, Schertzer JD, Steinberg GR (2020) Bacteria transmit metformin-associated lifespan extension. Nat Rev Endocrinol 16:9-10. -
  12. El-Sayed SM, Ibrahim HM (2019) Effect of high-fat diet-induced obesity on thyroid gland structure in female rats and the possible ameliorating effect of metformin therapy. Folia Morphol (Warsz). 2019 Sep 6. doi: 10.5603/FM.a2019.0100. -
  13. Hartman SJ, Nelson SH, Marinac CR, Natarajan L, Parker BA, Patterson RE (2019) The effects of weight loss and metformin on cognition among breast cancer survivors: Evidence from the Reach for Health study. Psychooncology 28:1640-46. -
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MitoPedia: mitObesity drugs


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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 and glycerophosphate dehydrogenase complex.
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.
Healthy reference population     Body mass excess         BFE         BME cutoffs         BMI         H         M         VO2max         mitObesity drugs

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MitoPedia:mitObesity drug