Advertisement

Mitochondrial dynamics in exercise physiology

  • Tomohiro Tanaka
  • Akiyuki Nishimura
  • Kazuhiro Nishiyama
  • Takumi Goto
  • Takuro Numaga-Tomita
  • Motohiro NishidaEmail author
Invited Review
Part of the following topical collections:
  1. Invited review

Abstract

A growing body of evidence suggests that exercise shows pleiotropic effects on the maintenance of systemic homeostasis through mitochondria. Dysregulation of mitochondrial dynamism is associated with metabolic inflexibility, resulting in many of the metabolic diseases and aging. Studies have suggested that exercise prevents and delays the progression of mitochondrial dysfunction by improving mitochondrial metabolism, biogenesis, and quality control. Exercise modulates functions of mitochondrial dynamics-regulating proteins through post-translational modification mechanisms. In this review, we discuss the putative mechanisms underlying maintenance of mitochondrial homeostasis by exercise, especially focusing on the post-translational modifications of several signaling proteins contributing to mitochondrial biogenesis, autophagy or mitophagy flux, and fission/fusion cycle. We also introduce novel small molecules that can potentially mimic exercise therapy through preserving mitochondrial dynamism. These recent advancements in the field of mitochondrial biology may lead to a greater understanding of exercise signaling.

Keywords

Mitochondrial dynamics Quality control Metabolism Redox biology Drug design 

Notes

References

  1. 1.
    Akaike T, Ida T, Wei FY, Nishida M, Kumagai Y, Alam MM, Ihara H, Sawa T, Matsunaga T, Kasamatsu S, Nishimura A, Morita M, Tomizawa K, Nishimura A, Watanabe S, Inaba K, Shima H, Tanuma N, Jung M, Fujii S, Watanabe Y, Ohmuraya M, Nagy P, Feelisch M, Fukuto JM, Motohashi H (2017) Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. Nat Commun 8.  https://doi.org/10.1038/s41467-017-01311-y
  2. 2.
    Akita M, Suzuki-Karasaki M, Fujiwara K, Nakagawa C, Soma M, Yoshida Y, Ochiai T, Tokuhashi Y, Suzuki-Karasaki Y (2014) Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis. Int J Oncol 45:1901–1902.  https://doi.org/10.3892/ijo.2014.2608
  3. 3.
    Alam TI, Kanki T, Muta T, Ukaji K, Abe Y, Nakayama H, Takio K, Hamasaki N, Kang D (2003) Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res 31:1640–1645Google Scholar
  4. 4.
    Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu P-H, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1:259–271.  https://doi.org/10.1016/j.cmet.2005.03.002
  5. 5.
    Archer SL (2013) Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 369:2236–2251.  https://doi.org/10.1056/NEJMra1215233 CrossRefGoogle Scholar
  6. 6.
    Arnér ESJ, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267(20):6102–6109Google Scholar
  7. 7.
    Ashrafi G, Schwarz TL (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 20:31–42Google Scholar
  8. 8.
    Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, Gräber S, Kovacs I, Lee WD, Waggoner J, Cui J, White AD, Bossy B, Martinou JC, Youle RJ, Lipton SA, Ellisman MH, Perkins GA, Bossy-Wetzel E (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 25:3900–3911.  https://doi.org/10.1038/sj.emboj.7601253
  9. 9.
    Bengtsson J, Gustafsson T, Widegren U, Jansson E, Sundberg CJ (2001) Mitochondrial transcription factor A and respiratory complex IV increase in response to exercise training in humans. Pflugers Arch Eur J Physiol 443:61–11.  https://doi.org/10.1007/s004240100628
  10. 10.
    Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, Ganie SA (2015) Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother 74:101–110Google Scholar
  11. 11.
    Booth FW, Kelso JR (1973) Cytochrome oxidase of skeletal muscle: adaptive response to chronic disuse. Can J Physiol Pharmacol 51:679–681.  https://doi.org/10.1139/y73-102
  12. 12.
    Booth M (2000) Assessment of physical activity: an international perspective. Res Q Exerc Sport 71:114–120.  https://doi.org/10.1080/02701367.2000.11082794
  13. 13.
    Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, Cherok E, Khalil A, Yadava N, Ge SX, Francis TC, Kennedy NW, Picton LK, Kumar T, Uppuluri S, Miller AM, Itoh K, Karbowski M, Sesaki H, Hill RB, Polster BM (2017) The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species. Dev Cell 40:583–594.e6.  https://doi.org/10.1016/j.devcel.2017.02.020 CrossRefGoogle Scholar
  14. 14.
    Bossy B, Petrilli A, Klinglmayr E, Chen J, Lütz-Meindl U, Knott AB, Masliah E, Schwarzenbacher R, Bossy-Wetzel E (2010) S-nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer’s disease. J Alzheimers Dis 20.  https://doi.org/10.3233/JAD-2010-100552
  15. 15.
    Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H (2018) Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep 6:e13651.  https://doi.org/10.14814/phy2.13651
  16. 16.
    Brunmair 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.  https://doi.org/10.2337/diabetes.53.4.1052
  17. 17.
    Busquets-Cortés C, Capó X, Martorell M, Tur JA, Sureda A, Pons A (2017) Training and acute exercise modulates mitochondrial dynamics in football players’ blood mononuclear cells. Eur J Appl Physiol 117:1977–1987.  https://doi.org/10.1007/s00421-017-3684-z
  18. 18.
    Campbell CT, Kolesar JE, Kaufman BA (2012) Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number. Biochim Biophys Acta - Gene Regul Mech 1819:921–929Google Scholar
  19. 19.
    Cantó C, 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 458:1056–1060.  https://doi.org/10.1038/nature07813
  20. 20.
    Cantó C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11:213–219.  https://doi.org/10.1016/j.cmet.2010.02.006
  21. 21.
    Cao J, Meng S, Chang E, Beckwith-Fickas K, Xiong L, Cole RN, Radovick S, Wondisford FE, He L (2014) Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). J Biol Chem 289:20435–20446.  https://doi.org/10.1074/jbc.M114.567271
  22. 22.
    Cartoni R, Léger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Dériaz O, Zorzano A, Gobelet C, Kralli A, Russell AP (2005) Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exercise. J Physiol 567:349–358.  https://doi.org/10.1113/jphysiol.2005.092031
  23. 23.
    Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, Nunnari J (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 2:193–204.  https://doi.org/10.1016/j.devcel.2007.11.019
  24. 24.
    Cerveró C, Montull N, Tarabal O, Piedrafita L, Esquerda JE, Calderó J (2016) Chronic treatment with the AMPK agonist AICAR prevents skeletal muscle pathology but fails to improve clinical outcome in a mouse model of severe spinal muscular atrophy. Neurotherapeutics 13:198–216.  https://doi.org/10.1007/s13311-015-0399-x
  25. 25.
    Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282:21583–21587  https://doi.org/10.1074/jbc.C700083200
  26. 26.
    Chau JY, Grunseit AC, Chey T, Stamatakis E, Brown WJ, Matthews CE, Bauman AE, Van Der Ploeg HP (2013) Daily sitting time and all-cause mortality: a meta-analysis. PLoS One 8:e80000.  https://doi.org/10.1371/journal.pone.0080000
  27. 27.
    Chaube B, Bhat MK (2016) AMPK, a key regulator of metabolic/energy homeostasis and mitochondrial biogenesis in cancer cells. Cell Death Dis 7:e2044Google Scholar
  28. 28.
    Chen C, Hood D (2016) Parkin-mediated mitophagy in skeletal muscle with aging and exercise. FASEB J Abstract Number 764.3Google Scholar
  29. 29.
    Chen CCW, Erlich AT, Crilly MJ, Hood DA (2018) Parkin is required for exercise-induced mitophagy in muscle: impact of aging. Am J Physiol Metab.  https://doi.org/10.1152/ajpendo.00391.2017
  30. 30.
    Chen CCW, Erlich AT, Hood DA (2018) Role of Parkin and endurance training on mitochondrial turnover in skeletal muscle. Skelet Muscle.  https://doi.org/10.1186/s13395-018-0157-y
  31. 31.
    Chen H, Chan DC (2009) Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases. Hum Mol Genet.  https://doi.org/10.1093/hmg/ddp326
  32. 32.
    Chen Y, Dorn GW (2013) PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria. Science (80- ).  https://doi.org/10.1126/science.1231031
  33. 33.
    Cheng AJ, Yamada T, Rassier DE, Andersson DC, Westerblad H, Lanner JT (2016) Reactive oxygen/nitrogen species and contractile function in skeletal muscle during fatigue and recovery. J Physiol.  https://doi.org/10.1113/JP270650
  34. 34.
    Cho D-HH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science (80- ).  https://doi.org/10.1126/science.1171091
  35. 35.
    Choi HC, Song P, Xie Z, Wu Y, Xu J, Zhang M, Dong Y, Wang S, Lau K, Zou M-H (2008) Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo. J Biol Chem.  https://doi.org/10.1074/jbc.M803020200
  36. 36.
    Chrysostomou V, Rezania F, Trounce IA, Crowston JG (2013) Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol.  https://doi.org/10.1016/j.coph.2012.09.008
  37. 37.
    Circu ML, Aw TY (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 48:749–762Google Scholar
  38. 38.
    Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, De Cabo R, Sinclair DA (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science (80- ). doi:  https://doi.org/10.1126/science.1099196
  39. 39.
    Cortassa S, O’Rourke B, Aon MA (2014) Redox-optimized ROS balance and the relationship between mitochondrial respiration and ROS. Biochim Biophys Acta Bioenerg.  https://doi.org/10.1016/j.bbabio.2013.11.007
  40. 40.
    Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep.  https://doi.org/10.1038/sj.embor.7401062
  41. 41.
    Dethlefsen MM, Halling JF, Møller HD, Plomgaard P, Regenberg B, Ringholm S, Pilegaard H (2018) Regulation of apoptosis and autophagy in mouse and human skeletal muscle with aging and lifelong exercise training. Exp Gerontol.  https://doi.org/10.1016/j.exger.2018.07.011
  42. 42.
    Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879Google Scholar
  43. 43.
    Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, McCann L, Lewis W, Harrison DG, Dikalov SI (2010) Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res.  https://doi.org/10.1161/CIRCRESAHA.109.214601
  44. 44.
    Ding WX, Yin XM (2012) Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem 393:547–564Google Scholar
  45. 45.
    Diotte NM, Xiong Y, Gao J, Chua BHL, Ho YS (2009) Attenuation of doxorubicin-induced cardiac injury by mitochondrial glutaredoxin 2. Biochim Biophys Acta - Mol Cell Res.  https://doi.org/10.1016/j.bbamcr.2008.10.014
  46. 46.
    Disatnik MH, Ferreira JCB, Campos JC, Gomes KS, Dourado PMM, Qi X, Mochly-Rosen D (2013) Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long-term cardiac dysfunction. J Am Heart Assoc.  https://doi.org/10.1161/JAHA.113.000461
  47. 47.
    Dong K, Wu M, Liu X, Huang Y, Zhang D, Wang Y, Yan LJ, Shi D (2016) Glutaredoxins concomitant with optimal ROS activate AMPK through S-glutathionylation to improve glucose metabolism in type 2 diabetes. Free Radic Biol Med.  https://doi.org/10.1016/j.freeradbiomed.2016.10.007
  48. 48.
    Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK (2009) Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc 41:459–471Google Scholar
  49. 49.
    Dröse S, Brandt U, Wittig I (2014) Mitochondrial respiratory chain complexes as sources and targets of thiol-based redox-regulation. Biochim Biophys Acta - Proteins Proteomics 1844:1344–1354Google Scholar
  50. 50.
    Duca FA, Côté CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, Lam TKT (2015) Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med.  https://doi.org/10.1038/nm.3787
  51. 51.
    Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, Hultenby K, Rustin P, Gustafsson CM, Larsson NG (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet.  https://doi.org/10.1093/hmg/ddh109
  52. 52.
    El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem.  https://doi.org/10.1074/jbc.275.1.223
  53. 53.
    Emerit J, Edeas M, Bricaire F (2004) Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 58:39–46Google Scholar
  54. 54.
    Fan W, Evans RM (2017) Exercise mimetics: impact on health and performance. Cell Metab 25:242–247.  https://doi.org/10.1016/j.cmet.2016.10.022 CrossRefGoogle Scholar
  55. 55.
    Farah C, Kleindienst A, Bolea G, Meyer G, Gayrard S, Geny B, Obert P, Cazorla O, Tanguy S, Reboul C (2013) Exercise-induced cardioprotection: a role for eNOS uncoupling and NO metabolites. Basic Res Cardiol.  https://doi.org/10.1007/s00395-013-0389-2
  56. 56.
    Fealy CE, Mulya A, Lai N, Kirwan JP (2014) Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle. J Appl Physiol 117:239–245.  https://doi.org/10.1152/japplphysiol.01064.2013 CrossRefGoogle Scholar
  57. 57.
    Ferrara N, Rinaldi B, Corbi G, Conti V, Stiuso P, Boccuti S, Rengo G, Rossi F, Filippelli A (2008) Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Res.  https://doi.org/10.1089/rej.2007.0576
  58. 58.
    Ferree AW, Trudeau K, Zik E, Benador IY, Twig G, Gottlieb RA, Shirihai OS (2013) MitoTimer probe reveals the impact of autophagy, fusion, and motility on subcellular distribution of young and old mitochondrial protein and on relative mitochondrial protein age. Autophagy.  https://doi.org/10.4161/auto.26503
  59. 59.
    Figueira TR, Barros MH, Camargo AA, Castilho RF, Ferreira JCB, Kowaltowski AJ, Sluse FE, Souza-Pinto NC, Vercesi AE (2013) Mitochondria as a source of reactive oxygen and nitrogen species: from molecular mechanisms to human health. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2012.4729
  60. 60.
    Fu T, Xu Z, Liu L, Guo Q, Wu H, Liang X, Zhou D, Xiao L, Liu L, Liu Y, Zhu MS, Chen Q, Gan Z (2018) Mitophagy directs muscle-adipose crosstalk to alleviate dietary obesity. Cell Rep.  https://doi.org/10.1016/j.celrep.2018.03.127
  61. 61.
    Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen Z-P, O’Neill HM, Ford RJ, Palanivel R, O’Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JRB, van Denderen BJ, Kemp BE, Steinberg GR (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med.  https://doi.org/10.1038/nm.3372
  62. 62.
    Gallogly MM, Shelton MD, Qanungo S, Pai HV, Starke DW, Hoppel CL, Lesnefsky EJ, Mieyal JJ (2010) Glutaredoxin regulates apoptosis in cardiomyocytes via NFκB targets Bcl-2 and Bcl-xL: implications for cardiac aging. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2009.2791
  63. 63.
    Ghahremani R, Damirchi A, Salehi I, Komaki A, Esposito F (2018) Mitochondrial dynamics as an underlying mechanism involved in aerobic exercise training-induced cardioprotection against ischemia-reperfusion injury. Life Sci.  https://doi.org/10.1016/j.lfs.2018.10.035
  64. 64.
    Gledhill JR, Montgomery MG, Leslie AGW, Walker JE (2007) Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci.  https://doi.org/10.1073/pnas.0706290104
  65. 65.
    Gohil K, Viguie C, Stanley WC, Brooks G a, Packer L (1988) Blood glutathione oxidation during human exercise. J Appl Phsysiology.  https://doi.org/10.1249/00005768-198704001-00249
  66. 66.
    Gomez-Cabrera MC, Salvador-Pascual A, Cabo H, Ferrando B, Vina J (2015) Redox modulation of mitochondriogenesis in exercise. Does antioxidant supplementation blunt the benefits of exercise training? Free Radic Biol Med 86:37–46Google Scholar
  67. 67.
    Goncalves RLS, Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Brand MD (2015) Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise. J Biol Chem 290:209–227Google Scholar
  68. 68.
    Greenway MJ, Andersen PM, Russ G, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH, Hardiman O (2006) ANG mutations segregate with familial and “sporadic” amyotrophic lateral sclerosis. Nat Genet.  https://doi.org/10.1038/ng1742
  69. 69.
    Greggio C, Jha P, Kulkarni SS, Lagarrigue S, Broskey NT, Boutant M, Wang X, Conde Alonso S, Ofori E, Auwerx J, Cantó C, Amati F (2017) Enhanced respiratory chain supercomplex formation in response to exercise in human skeletal muscle. Cell Metab.  https://doi.org/10.1016/j.cmet.2016.11.004
  70. 70.
    Grohm J, Kim SW, Mamrak U, Tobaben S, Cassidy-Stone A, Nunnari J, Plesnila N, Culmsee C (2012) Inhibition of Drp1 provides neuroprotection in vitro and in vivo. Cell Death Differ.  https://doi.org/10.1038/cdd.2012.18
  71. 71.
    Guo X, Disatnik M, Monbureau M, Shamloo M, Mochly-rosen D, Qi X (2013) Inhibition of mitochondrial fragmentation diminishes Huntington’ s disease–associated neurodegeneration. J Clin Invest.  https://doi.org/10.1172/JCI70911DS1
  72. 72.
    Halling JF, Ringholm S, Olesen J, Prats C, Pilegaard H (2017) Exercise training protects against aging-induced mitochondrial fragmentation in mouse skeletal muscle in a PGC-1α dependent manner. Exp Gerontol.  https://doi.org/10.1016/j.exger.2017.05.020
  73. 73.
    Hamilton MT, Healy GN, Dunstan DW, Zderic TW, Owen N (2008) Too little exercise and too much sitting: inactivity physiology and the need for new recommendations on sedentary behavior. Curr Cardiovasc Risk Rep.  https://doi.org/10.1007/s12170-008-0054-8
  74. 74.
    Han Y, Wang Q, Song P, Zhu Y, Zou MH (2010) Redox regulation of the AMP-activated protein kinase. PLoS One.  https://doi.org/10.1371/journal.pone.0015420
  75. 75.
    Harber MP, Kaminsky LA, Arena R, Blair SN, Franklin BA, Myers J, Ross R (2017) Impact of cardiorespiratory fitness on all-cause and disease-specific mortality: advances since 2009. Prog Cardiovasc Dis 60:11–20Google Scholar
  76. 76.
    Hardie DG (2011) AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895–1908Google Scholar
  77. 77.
    Hardie DG, Ross FA, Hawley SA (2012) AMP-activated protein kinase: a target for drugs both ancient and modern. Chem Biol 19:1222–1236Google Scholar
  78. 78.
    Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science (80- ).  https://doi.org/10.1126/science.1215327
  79. 79.
    Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM, Hardie DG (2010) Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab.  https://doi.org/10.1016/j.cmet.2010.04.001
  80. 80.
    He L, Wondisford FE (2015) Metformin action: concentrations matter. Cell Metab 21:159–162Google Scholar
  81. 81.
    Hernandez G, Thornton C, Stotland A, Lui D, Sin J, Ramil J, Magee N, Andres A, Quarato G, Carreira RS, Sayen MR, Wolkowicz R, Gottlieb RA (2013) MitoTimer: a novel tool for monitoring mitochondrial turnover. Autophagy.  https://doi.org/10.4161/auto.26501
  82. 82.
    Herzig S, Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19:121–135Google Scholar
  83. 83.
    Hewitt VL, Whitworth AJ (2017) Mitochondrial fission and fusion. In: Parkinson’s disease: molecular mechanisms underlying pathologyGoogle Scholar
  84. 84.
    Hill BG, Higdon AN, Dranka BP, Darley-Usmar VM (2010) Regulation of vascular smooth muscle cell bioenergetic function by protein glutathiolation. Biochim Biophys Acta Bioenerg.  https://doi.org/10.1016/j.bbabio.2009.11.005
  85. 85.
    Hoffman NJ, Parker BL, Chaudhuri R, Fisher-Wellman KH, Kleinert M, Humphrey SJ, Yang P, Holliday M, Trefely S, Fazakerley DJ, Stöckli J, Burchfield JG, Jensen TE, Jothi R, Kiens B, Wojtaszewski JFP, Richter EA, James DE (2015) Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab.  https://doi.org/10.1016/j.cmet.2015.09.001
  86. 86.
    Holloszy JO (1967) Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 242:2278–2282Google Scholar
  87. 87.
    Holloszy JO (2008) Regulation by exercise of skeletal muscle content of mitochondria and GLUT4. In: Journal of Physiology and Pharmacology 59 Suppl 7:5–18Google Scholar
  88. 88.
    Holloszy JO (2011) Regulation of mitochondrial biogenesis and GLUT4 expression by exercise. Compr Physiol 1:921–940Google Scholar
  89. 89.
    Hood DA (2001) Plasticity in skeletal, cardiac, and smooth muscle invited review: contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol.  https://doi.org/10.1152/jappl.2001.90.3.1137
  90. 90.
    Horie T, Ono K, Nagao K, Nishi H, Kinoshita M, Kawamura T, Wada H, Shimatsu A, Kita T, Hasegawa K (2008) Oxidative stress induces GLUT4 translocation by activation of PI3-K/Akt and dual AMPK kinase in cardiac myocytes. J Cell Physiol.  https://doi.org/10.1002/jcp.21353
  91. 91.
    Hou X, Song J, Li XN, Zhang L, Wang XL, Chen L, Shen YH (2010) Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun.  https://doi.org/10.1016/j.bbrc.2010.04.017
  92. 92.
    Irrcher I, Ljubicic V, Hood DA (2008) Interactions between ROS and AMP kinase activity in the regulation of PGC-1 transcription in skeletal muscle cells. AJP Cell Physiol.  https://doi.org/10.1152/ajpcell.00267.2007
  93. 93.
    Itoh K, Nakamura K, Iijima M, Sesaki H (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23:64–71Google Scholar
  94. 94.
    Jäger SS, Handschin CC, St-Pierre JJ, Spiegelman BMBM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. PNAS.  https://doi.org/10.1073/pnas.0705070104
  95. 95.
    Jamart C, Benoit N, Raymackers JM, Kim HJ, Kim CK, Francaux M (2012) Autophagy-related and autophagy-regulatory genes are induced in human muscle after ultraendurance exercise. Eur J Appl Physiol.  https://doi.org/10.1007/s00421-011-2287-3
  96. 96.
    Jheng H-F, Tsai P-J, Guo S-M, Kuo L-H, Chang C-S, Su I-J, Chang C-R, Tsai Y-S (2012) Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol 32:309–319.  https://doi.org/10.1128/MCB.05603-11 CrossRefGoogle Scholar
  97. 97.
    Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell.  https://doi.org/10.1016/j.molcel.2005.03.027
  98. 98.
    Jørgensen SB, Richter EA, Wojtaszewski JFP (2006) Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise. J Physiol 574:17–31Google Scholar
  99. 99.
    Joshi AU, Saw NL, Vogel H, Cunnigham AD, Shamloo M, Mochly-Rosen D (2018) Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol Med e8166.  https://doi.org/10.15252/emmm.201708166
  100. 100.
    Sun JJ, Il JS, Young PJ, Young LJ, Cheol LS, Jung CK, Moon JJ (2016) Autophagy plays a role in skeletal muscle mitochondrial biogenesis in an endurance exercise-trained condition. J Physiol Sci.  https://doi.org/10.1007/s12576-016-0440-9
  101. 101.
    Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25Google Scholar
  102. 102.
    Kang SWS, Haydar G, Taniane C, Farrell G, Arias IM, Lippincott-Schwartz J, Fu D (2016) AMPK activation prevents and reverses drug-induced mitochondrial and hepatocyte injury by promoting mitochondrial fusion and function. PLoS One.  https://doi.org/10.1371/journal.pone.0165638
  103. 103.
    Keadle SK, Conroy DE, Buman MP, Dunstan DW, Matthews CE (2017) Targeting reductions in sitting time to increase physical activity and improve health. Med Sci Sports Exerc.  https://doi.org/10.1249/MSS.0000000000001257
  104. 104.
    Kim EJ, Jung SN, Son KH, Kim SR, Ha TY, Park MG, Jo IG, Park JG, Choe W, Kim SS, Ha J (2007) Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase. MolPharmacol.  https://doi.org/10.1124/mol.107.034447.disorders
  105. 105.
    Kim H, Scimia MC, Wilkinson D, Trelles RD, Wood MR, Bowtell D, Dillin A, Mercola M, Ronai ZA (2011) Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Mol Cell 44:532–544.  https://doi.org/10.1016/j.molcel.2011.08.045 CrossRefGoogle Scholar
  106. 106.
    Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253Google Scholar
  107. 107.
    Kim Y-M, Youn S-W, Sudhahar V, Das A, Chandhri R, Cuervo Grajal H, Kweon J, Leanhart S, He L, Toth PT, Kitajewski J, Rehman J, Yoon Y, Cho J, Fukai T, Ushio-Fukai M (2018) Redox regulation of mitochondrial fission protein Drp1 by protein disulfide isomerase limits endothelial senescence. Cell Rep 23:3565–3578.  https://doi.org/10.1016/j.celrep.2018.05.054 CrossRefGoogle Scholar
  108. 108.
    Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun.  https://doi.org/10.1016/j.bbrc.2008.10.104
  109. 109.
    Kirkwood SP, Packer L, Brooks GA (1987) Effects of endurance training on a mitochondrial reticulum in limb skeletal muscle. Arch Biochem Biophys.  https://doi.org/10.1016/0003-9861(87)90296-7
  110. 110.
    Kitaoka Y, Nakazato K, Ogasawara R (2016) Combined effects of resistance training and calorie restriction on mitochondrial fusion and fission proteins in rat skeletal muscle. J Appl Physiol.  https://doi.org/10.1152/japplphysiol.00465.2016
  111. 111.
    Kiyuna LA, Albuquerque RP e., Chen CH, Mochly-Rosen D, Ferreira JCB (2018) Targeting mitochondrial dysfunction and oxidative stress in heart failure: challenges and opportunities. Free Radic Biol Med 129:155–168Google Scholar
  112. 112.
    Ko TH, Marquez JC, Kim HK, Jeong SH, Lee SR, Youm JB, Song IS, Seo DY, Kim HJ, Won DN, Cho KI, Choi MG, Rhee BD, Ko KS, Kim N, Won JC, Han J (2018) Resistance exercise improves cardiac function and mitochondrial efficiency in diabetic rat hearts. Pflugers Arch Eur J Physiol.  https://doi.org/10.1007/s00424-017-2076-x
  113. 113.
    Koltai E, Hart N, Taylor AW, Goto S, Ngo JK, Davies KJA, Radak Z (2012) Age-associated declines in mitochondrial biogenesis and protein quality control factors are minimized by exercise training. AJP Regul Integr Comp Physiol.  https://doi.org/10.1152/ajpregu.00337.2011
  114. 114.
    Konagaya Y, Terai K, Hirao Y, Takakura K, Imajo M, Kamioka Y, Sasaoka N, Kakizuka A, Sumiyama K, Asano T, Matsuda M (2017) A highly sensitive FRET biosensor for AMPK exhibits heterogeneous AMPK responses among cells and organs. Cell Rep.  https://doi.org/10.1016/j.celrep.2017.10.113
  115. 115.
    Korwitz A, Merkwirth C, Richter-Dennerlein R, Tröder SE, Sprenger HG, Quirós PM, López-Otín C, Rugarli EI, Langer T (2016) Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria. J Cell Biol.  https://doi.org/10.1083/jcb.201507022
  116. 116.
    Kretzschmar M, Müller D (1993) Aging, training and exercise: a review of effects on plasma glutathione and lipid peroxides. Sport Med Eval Res Exerc Sci Sport Med 15:196–209Google Scholar
  117. 117.
    Laker RC, Drake JC, Wilson RJ, Lira VA, Lewellen BM, Ryall KA, Fisher CC, Zhang M, Saucerman JJ, Goodyear LJ, Kundu M, Yan Z (2017) Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat Commun.  https://doi.org/10.1038/s41467-017-00520-9
  118. 118.
    Laker RC, Xu P, Ryall KA, Sujkowski A, Kenwood BM, Chain KH, Zhang M, Royal MA, Hoehn KL, Driscoll M, Adler PN, Wessells RJ, Saucerman JJ, Yan Z (2014) A novel mitotimer reporter gene for mitochondrial content, structure, stress, and damage in vivo. J Biol Chem.  https://doi.org/10.1074/jbc.M113.530527
  119. 119.
    Lantier L, Fentz J, Mounier R, Leclerc J, Treebak JT, Pehmøller C, Sanz N, Sakakibara I, Saint-Amand E, Rimbaud S, Maire P, Marette A, Ventura-Clapier R, Ferry A, Wojtaszewski JFP, Foretz M, Viollet B (2014) AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. FASEB J.  https://doi.org/10.1096/fj.14-250449
  120. 120.
    Larsen FJ, Schiffer TA, Ortenblad N, Zinner C, Morales-Alamo D, Willis SJ, Calbet JA, Holmberg HC, Boushel R (2015) High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation. FASEB J.  https://doi.org/10.1096/fj.15-276857
  121. 121.
    Lee-Young RS, Ayala JE, Hunley CF, James FD, Bracy DP, Kang L, Wasserman DH (2010) Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo. AJP Regul Integr Comp Physiol.  https://doi.org/10.1152/ajpregu.00004.2010
  122. 122.
    Lee JE, Westrate LM, Wu H, Page C, Voeltz GK (2016) Multiple dynamin family members collaborate to drive mitochondrial division. Nature.  https://doi.org/10.1038/nature20555
  123. 123.
    Lee S, Sterky FH, Mourier A, Terzioglu M, Cullheim S, Olson L, Larsson NG (2012) Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons. Hum Mol Genet.  https://doi.org/10.1093/hmg/dds352
  124. 124.
    Li J, Wang Y, Wang Y, Wen X, Ma XN, Chen W, Huang F, Kou J, Qi LW, Liu B, Liu K (2015) Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction. J Mol Cell Cardiol.  https://doi.org/10.1016/j.yjmcc.2015.07.010
  125. 125.
    Li Y, Nourbakhsh N, Hall E, Hepokoski M, Pham H, Thomas J, Singh P (2016) Protective role of AMPK in sepsis associated AKI. FASEB J Abstract Number:1217.18Google Scholar
  126. 126.
    Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature.  https://doi.org/10.1038/nature00904
  127. 127.
    Lira VA, Brown DL, Lira AK, Kavazis AN, Soltow QA, Zeanah EH, Criswell DS (2010) Nitric oxide and AMPK cooperatively regulate PGC-1α in skeletal muscle cells. J Physiol.  https://doi.org/10.1113/jphysiol.2010.194035
  128. 128.
    Lira VA, Okutsu M, Zhang M, Greene NP, Laker RC, Breen DS, Hoehn KL, Yan Z (2013) Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J.  https://doi.org/10.1096/fj.13-228486
  129. 129.
    Little JP, Gillen JB, Percival ME, Safdar A, Tarnopolsky MA, Punthakee Z, Jung ME, Gibala MJ (2011) Low-volume high-intensity interval training reduces hyperglycemia and increases muscle mitochondrial capacity in patients with type 2 diabetes. J Appl Physiol.  https://doi.org/10.1152/japplphysiol.00921.2011
  130. 130.
    Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, Huang L, Xue P, Li B, Wang X, Jin H, Wang J, Yang F, Liu P, Zhu Y, Sui S, Chen Q (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol.  https://doi.org/10.1038/ncb2422
  131. 131.
    Lu B, Lee J, Nie X, Li M, Morozov YI, Venkatesh S, Bogenhagen DF, Temiakov D, Suzuki CK (2013) Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+Lon protease. Mol Cell.  https://doi.org/10.1016/j.molcel.2012.10.023
  132. 132.
    Lu J, Holmgren A (2014) The thioredoxin antioxidant system. Free Radic Biol Med.  https://doi.org/10.1016/j.freeradbiomed.2013.07.036
  133. 133.
    Lu Q, Ding K, Frosch MP, Jones S, Wolfe M, Xia W, Lanford GW (2010) Alzheimer’s disease-linked presenilin mutation (PS1M146L) induces filamin expression and γ-secretase independent redistribution. J Alzheimers Dis.  https://doi.org/10.3233/JAD-2010-100585
  134. 134.
    Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature.  https://doi.org/10.1038/nature13270
  135. 135.
    Mailloux RJ, Xuan JY, McBride S, Maharsy W, Thorn S, Holterman CE, Kennedy CRJ, Rippstein P, DeKemp R, Da Silva J, Nemer M, Lou M, Harper ME (2014) Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions. J Biol Chem doi:  https://doi.org/10.1074/jbc.M114.550574
  136. 136.
    Mansueto G, Armani A, Viscomi C, D’Orsi L, De Cegli R, Polishchuk E V., Lamperti C, Di Meo I, Romanello V, Marchet S, Saha PK, Zong H, Blaauw B, Solagna F, Tezze C, Grumati P, Bonaldo P, Pessin JE, Zeviani M, Sandri M, Ballabio A (2017) Transcription factor EB controls metabolic flexibility during exercise. Cell Metab doi:  https://doi.org/10.1016/j.cmet.2016.11.003
  137. 137.
    Marchi S, Giorgi C, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Missiroli S, Patergnani S, Poletti F, Rimessi A, Duszynski J, Wieckowski MR, Pinton P (2012) Mitochondria-Ros crosstalk in the control of cell death and aging. J Signal Transduct doi:  https://doi.org/10.1155/2012/329635
  138. 138.
    Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC (2009) Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2009.2695
  139. 139.
    Marques-Aleixo I, Santos-Alves E, Torrella JR, Oliveira PJ, Magalhães J, Ascensão A (2018) Exercise and doxorubicin treatment modulate cardiac mitochondrial quality control signaling. Cardiovasc Toxicol.  https://doi.org/10.1007/s12012-017-9412-4
  140. 140.
    Marton O, Koltai E, Takeda M, Koch LG, Britton SL, Davies KJA, Boldogh I, Radak Z (2015) Mitochondrial biogenesis-associated factors underlie the magnitude of response to aerobic endurance training in rats. Pflugers Arch Eur J Physiol.  https://doi.org/10.1007/s00424-014-1554-7
  141. 141.
    Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, De Cabo R, Anderson RM (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun doi:  https://doi.org/10.1038/ncomms14063
  142. 142.
    McDonagh B (2016) Editorial: redox regulation in skeletal muscle aging and exercise. Front. Physiol 7Google Scholar
  143. 143.
    Mercken EM, Carboneau BA, Krzysik-Walker SM, De Cabo R (2012) Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res Rev 11:390–398Google Scholar
  144. 144.
    Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2008.2089
  145. 145.
    Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023Google Scholar
  146. 146.
    Miller MW, Knaub LA, Olivera-Fragoso LF, Keller AC, Balasubramaniam V, Watson PA, Reusch JEB (2013) Nitric oxide regulates vascular adaptive mitochondrial dynamics. AJP Hear Circ Physiol.  https://doi.org/10.1152/ajpheart.00987.2012
  147. 147.
    Mishra P, Chan DC (2016) Metabolic regulation of mitochondrial dynamics. J Cell Biol.  https://doi.org/10.1083/jcb.201511036
  148. 148.
    Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140:313–326Google Scholar
  149. 149.
    Muyderman H, Chen T (2014) Mitochondrial dysfunction in amyotrophic lateral sclerosis—a valid pharmacological target? Br J Pharmacol 171:2191–2205.  https://doi.org/10.1111/bph.12476 CrossRefGoogle Scholar
  150. 150.
    Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE (2002) Exercise capacity and mortality among men referred for exercise testing. N Engl J Med.  https://doi.org/10.1056/NEJMoa011858
  151. 151.
    Nakamura T, Cieplak P, Cho DH, Godzik A, Lipton SA (2010) S-Nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration. Mitochondrion.  https://doi.org/10.1016/j.mito.2010.04.007
  152. 152.
    Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM (2008) AMPK and PPARδ agonists are exercise mimetics. Cell.  https://doi.org/10.1016/j.cell.2008.06.051
  153. 153.
    Ni HM, Williams JA, Ding WX (2015) Mitochondrial dynamics and mitochondrial quality control. Redox Biol 4:6–13Google Scholar
  154. 154.
    Nikolaidis MG, Kyparos A, Spanou C, Paschalis V, Theodorou AA, Vrabas IS (2012) Redox biology of exercise: an integrative and comparative consideration of some overlooked issues. J Exp Biol.  https://doi.org/10.1242/jeb.067470
  155. 155.
    Nishimura A, Shimauchi T, Tanaka T, Shimoda K, Toyama T, Kitajima N, Ishikawa T, Shindo N, Numaga-tomita T, Yasuda S, Sato Y, Kuwahara K, Kumagai Y, Akaike T (2018) Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission–associated myocardial senescence. 5185.  https://doi.org/10.1126/scisignal.aat5185
  156. 156.
    O’Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jørgensen SB, Schertzer JD, Shyroka O, Kiens B, van Denderen BJ, Tarnopolsky MA, Kemp BE, Richter EA, Steinberg GR (2011) AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci U S A doi:  https://doi.org/10.1073/pnas.1105062108
  157. 157.
    Ong S-B, Hausenloy DJ (2010) Mitochondrial morphology and cardiovascular disease. Cardiovasc Res.  https://doi.org/10.1093/cvr/cvq237
  158. 158.
    Ouyang J, Parakhia RA, Ochs RS (2011) Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem.  https://doi.org/10.1074/jbc.M110.121806
  159. 159.
    OWEN MR, DORAN E, HALESTRAP AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J.  https://doi.org/10.1042/0264-6021:3480607
  160. 160.
    Parihar P, Solanki I, Mansuri ML, Parihar MS (2015) Mitochondrial sirtuins: emerging roles in metabolic regulations, energy homeostasis and diseases. Exp Gerontol 61:130–141Google Scholar
  161. 161.
    Patel AV, Bernstein L, Deka A, Feigelson HS, Campbell PT, Gapstur SM, Colditz GA, Thun MJ (2010) Leisure time spent sitting in relation to total mortality in a prospective cohort of US adults. Am J Epidemiol.  https://doi.org/10.1093/aje/kwq155
  162. 162.
    Pauly M, Daussin F, Burelle Y, Li T, Godin R, Fauconnier J, Koechlin-Ramonatxo C, Hugon G, Lacampagne A, Coisy-Quivy M, Liang F, Hussain S, Matecki S, Petrof BJ (2012) AMPK activation stimulates autophagy and ameliorates muscular dystrophy in the mdx mouse diaphragm. Am J Pathol.  https://doi.org/10.1016/j.ajpath.2012.04.004
  163. 163.
    Pedersen BK, Saltin B (2015) Exercise as medicine—evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sport.  https://doi.org/10.1111/sms.12581
  164. 164.
    Penedo FJ, Dahn JR (2005) Exercise and well-being: a review of mental and physical health benefits associated with physical activity. Curr Opin Psychiatry 18:189–193Google Scholar
  165. 165.
    Penman KA (1970) Human striated muscle ultrastructural changes accompanying increased strength without hypertrophy. Res Q Am Assoc Heal Phys Educ Recreat.  https://doi.org/10.1080/10671188.1970.10614992
  166. 166.
    Perry CGR, Lally J, Holloway GP, Heigenhauser GJF, Bonen A, Spriet LL (2010) Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle. J Physiol.  https://doi.org/10.1113/jphysiol.2010.199448
  167. 167.
    Picca A, Lezza AMS (2015) Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions. Useful insights from aging and calorie restriction studies. Mitochondrion 25:67–75Google Scholar
  168. 168.
    Powers SK, Duarte J, Kavazis AN, Talbert EE (2010) Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol 95:1–9Google Scholar
  169. 169.
    Qi X, Qvit N, Su Y-C, Mochly-Rosen D (2013) A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci.  https://doi.org/10.1242/jcs.114439
  170. 170.
    Quintero M, Colombo SL, Godfrey A, Moncada S (2006) Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci.  https://doi.org/10.1073/pnas.0601026103
  171. 171.
    Radak Z, Zhao Z, Koltai E, Ohno H, Atalay M (2013) Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2011.4498
  172. 172.
    Rappold PM, Cui M, Grima JC, Fan RZ, De Mesy-Bentley KL, Chen L, Zhuang X, Bowers WJ, Tieu K (2014) Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nat Commun.  https://doi.org/10.1038/ncomms6244
  173. 173.
    Ribas V, García-Ruiz C, Fernández-Checa JC (2014) Glutathione and mitochondria. Front. Pharmacol 5:151Google Scholar
  174. 174.
    Ristow M, Schmeisser K (2014) Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose-Response.  https://doi.org/10.2203/dose-response.13-035.Ristow
  175. 175.
    Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Bluher M (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci.  https://doi.org/10.1073/pnas.0903485106
  176. 176.
    Rocchi A, He C (2017) Regulation of exercise-induced autophagy in skeletal muscle. Curr Pathobiol Rep.  https://doi.org/10.1007/s40139-017-0135-9
  177. 177.
    Rocha AG, Franco A, Krezel AM, Rumsey JM, Alberti JM, Knight WC, Biris N, Zacharioudakis E, Janetka JW, Baloh RH, Kitsis RN, Mochly-Rosen D, Townsend RR, Gavathiotis E, Dorn GW (2018) MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science (80- ).  https://doi.org/10.1126/science.aao1785
  178. 178.
    Sakellariou GK, Vasilaki A, Palomero J, Kayani A, Zibrik L, McArdle A, Jackson MJ (2013) Studies of mitochondrial and nonmitochondrial sources implicate nicotinamide adenine dinucleotide phosphate oxidase(s) in the increased skeletal muscle superoxide generation that occurs during contractile activity. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2012.4623
  179. 179.
    Sandström ME, Zhang SJ, Bruton J, Silva JP, Reid MB, Westerblad H, Katz A (2006) Role of reactive oxygen species in contraction-mediated glucose transport in mouse skeletal muscle. J Physiol.  https://doi.org/10.1113/jphysiol.2006.110601
  180. 180.
    Schäfer M, Schäfer C, Ewald N, Piper HM, Noll T (2003) Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res.  https://doi.org/10.1161/01.RES.0000070882.81508.FC
  181. 181.
    Schiattarella GG, Boccella N, Paolillo R, Cattaneo F, Trimarco V, Franzone A, D’Apice S, Giugliano G, Rinaldi L, Borzacchiello D, Gentile A, Lombardi A, Feliciello A, Esposito G, Perrino C (2018) Loss of Akap1 exacerbates pressure overload-induced cardiac hypertrophy and heart failure. Front Physiol.  https://doi.org/10.3389/fphys.2018.00558
  182. 182.
    Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24:R453–62Google Scholar
  183. 183.
    Sebastian D, Hernandez-Alvarez MI, Segales J, Sorianello E, Munoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Oresic M, Pich S, Burcelin R, Palacin M, Zorzano A (2012) Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci.  https://doi.org/10.1073/pnas.1108220109
  184. 184.
    Sebastián D, Zorzano A (2018) Mitochondrial dynamics and metabolic homeostasis. Curr Opin Physiol 3:34–40Google Scholar
  185. 185.
    Shao D, Oka SI, Liu T, Zhai P, Ago T, Sciarretta S, Li H, Sadoshima J (2014) A redox-dependent mechanism for regulation of AMPK activation by thioredoxin1 during energy starvation. Cell Metab 19:232–245Google Scholar
  186. 186.
    Shao QQ, Zhang TP, Zhao WJ, Liu ZW, You L, Zhou L, Guo JC, Zhao YP (2016) Filamin a: insights into its exact role in cancers. Pathol Oncol Res 22:245–252Google Scholar
  187. 187.
    Sharma K (2015) Mitochondrial hormesis and diabetic complications. Diabetes.  https://doi.org/10.2337/db14-0874
  188. 188.
    Sheng ZH (2017) The interplay of axonal energy homeostasis and mitochondrial trafficking and anchoring. Trends Cell Biol 27:403–416Google Scholar
  189. 189.
    Shutt T, Geoffrion M, Milne R, McBride HM (2012) The intracellular redox state is a core determinant of mitochondrial fusion. EMBO Rep.  https://doi.org/10.1038/embor.2012.128
  190. 190.
    Skene JHP, Cleveland DW (2001) Hypoxia and lou gehrig. Nat Genet 28:107–108Google Scholar
  191. 191.
    Song M, Mihara K, Chen Y, Scorrano L, Dorn GW (2015) Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab.  https://doi.org/10.1016/j.cmet.2014.12.011
  192. 192.
    Sun M, Shen W, Zhong M, Wu P, Chen H, Lu A (2013) Nandrolone attenuates aortic adaptation to exercise in rats. Cardiovasc Res.  https://doi.org/10.1093/cvr/cvs423
  193. 193.
    Suwa M, Nakano H, Radak Z, Kumagai S (2008) Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor γ coactivator-1α protein expressions in rat skeletal muscle. Metabolism.  https://doi.org/10.1016/j.metabol.2008.02.017
  194. 194.
    Tadaishi M, Miura S, Kai Y, Kawasaki E, Koshinaka K, Kawanaka K, Nagata J, Oishi Y, Ezaki O (2011) Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1α mRNA: a role of β2-adrenergic receptor activation. Am J Physiol Endocrinol Metab.  https://doi.org/10.1152/ajpendo.00400.2010
  195. 195.
    Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, Ciciliot S, Soriano ME, Morbidoni V, Cerqua C, Loefler S, Kern H, Franceschi C, Salvioli S, Conte M, Blaauw B, Zampieri S, Salviati L, Scorrano L, Sandri M (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374–1389.e6.  https://doi.org/10.1016/j.cmet.2017.04.021 CrossRefGoogle Scholar
  196. 196.
    Theilen NT, Kunkel GH, Tyagi SC (2017) The role of exercise and TFAM in preventing skeletal muscle atrophy. J Cell Physiol 232:2348–2358Google Scholar
  197. 197.
    Thirupathi A, de Souza CT (2017) Multi-regulatory network of ROS: the interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise. J Physiol Biochem 73:487–494Google Scholar
  198. 198.
    Tolkovsky AM (2009) Mitophagy. Biochim. Biophys Acta - Mol Cell Res 1793:1508–1515Google Scholar
  199. 199.
    Tonin AM, Ferreira GC, Grings M, Viegas CM, Busanello EN, Amaral AU, Zanatta Â, Schuck PF, Wajner M (2010) Disturbance of mitochondrial energy homeostasis caused by the metabolites accumulating in LCHAD and MTP deficiencies in rat brain. Life Sci.  https://doi.org/10.1016/j.lfs.2010.04.003
  200. 200.
    Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ ResGoogle Scholar
  201. 201.
    Trachootham D, Lu W, Ogasawara MA, Valle NR-D, Huang P (2008) Redox regulation of cell survival. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2007.1957
  202. 202.
    Trewin A, Berry B, Wojtovich A (2018) Exercise and mitochondrial dynamics: keeping in shape with ROS and AMPK. Antioxidants.  https://doi.org/10.3390/antiox7010007
  203. 203.
    Trewin AJ, Levinger I, Parker L, Shaw CS, Serpiello FR, Anderson MJ, McConell GK, Hare DL, Stepto NK (2017) Acute exercise alters skeletal muscle mitochondrial respiration and H2O2 emission in response to hyperinsulinemic-euglycemic clamp in middle-aged obese men. PLoS One.  https://doi.org/10.1371/journal.pone.0188421
  204. 204.
    Trewin AJ, Lundell LS, Perry BD, Patil KV, Chibalin AV, Levinger I, McQuade LR, Stepto NK (2015) Effect of N -acetylcysteine infusion on exercise-induced modulation of insulin sensitivity and signaling pathways in human skeletal muscle. Am J Physiol - Endocrinol Metab.  https://doi.org/10.1152/ajpendo.00605.2014
  205. 205.
    Tsushima K, Bugger H, Wende AR, Soto J, Jenson GA, Tor AR, McGlauflin R, Kenny HC, Zhang Y, Souvenir R, Hu XX, Sloan CL, Pereira RO, Lira VA, Spitzer KW, Sharp TL, Shoghi KI, Sparagna GC, Rog-Zielinska EA, Kohl P, Khalimonchuk O, Schaffer JE, Abel ED (2018) Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission. Circ Res.  https://doi.org/10.1161/CIRCRESAHA.117.311307
  206. 206.
    Tullio F, Angotti C, Perrelli MG, Penna C, Pagliaro P (2013) Redox balance and cardioprotection. Basic Res Cardiol 108:392Google Scholar
  207. 207.
    Vainshtein A, Tryon LD, Pauly M, Hood DA (2015) Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am J Physiol - Cell Physiol.  https://doi.org/10.1152/ajpcell.00380.2014
  208. 208.
    Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84Google Scholar
  209. 209.
    Vanacore N, Cocco P, Fadda D, Dosemeci M (2010) Job strain, hypoxia and risk of amyotrophic lateral sclerosis: results from a death certificate study. Amyotroph Lateral Scler.  https://doi.org/10.3109/17482961003605796
  210. 210.
    Viña J, Gomez-Cabrera MC, Borras C, Froio T, Sanchis-Gomar F, Martinez-Bello VE, Pallardo FV (2009) Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev 61:1369–1374Google Scholar
  211. 211.
    Wadley AJ, Chen YW, Bennett SJ, Lip GYH, Turner JE, Fisher JP, Aldred S (2015) Monitoring changes in thioredoxin and over-oxidised peroxiredoxin in response to exercise in humans. Free Radic Res.  https://doi.org/10.3109/10715762.2014.1000890
  212. 212.
    Wadley GD, Nicolas MA, Hiam DS, McConell GK (2013) Xanthine oxidase inhibition attenuates skeletal muscle signaling following acute exercise but does not impair mitochondrial adaptations to endurance training. AJP Endocrinol Metab.  https://doi.org/10.1152/ajpendo.00568.2012
  213. 213.
    Wai T, García-Prieto J, Baker MJ, Merkwirth C, Benit P, Rustin P, Rupérez FJ, Barbas C, Ibañez B, Langer T (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science (80- ):350.  https://doi.org/10.1126/science.aad0116
  214. 214.
    Warburton DER, Bredin SSD (2017) Health benefits of physical activity: a systematic review of current systematic reviews. Curr Opin Cardiol 32:541–556Google Scholar
  215. 215.
    Warburton DER, Nicol CW, Bredin SSD (2006) Health benefits of physical activity: the evidence. CMAJ 174:801–809Google Scholar
  216. 216.
    Watanabe N, Zmijewski JW, Takabe W, Umezu-Goto M, Le Goffe C, Sekine A, Landar A, Watanabe A, Aoki J, Arai H, Kodama T, Murphy MP, Kalyanaraman R, Darley-Usmar VM, Noguchi N (2006) Activation of mitogen-activated protein kinases by lysophosphatidylcholine- induced mitochondrial reactive oxygen species generation in endothelial cells. Am J Pathol doi:  https://doi.org/10.2353/ajpath.2006.050648
  217. 217.
    Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884Google Scholar
  218. 218.
    Wicks KL, Hood DA (1991) Mitochondrial adaptations in denervated muscle: relationship to muscle performance. Am J Physiol - Cell Physiol.  https://doi.org/10.1083/JCB.153.2.319
  219. 219.
    Winder WW, Hardie DG (1996) Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol Metab.  https://doi.org/10.1152/ajpendo.1996.270.2.E299
  220. 220.
    Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO (2000) Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol.  https://doi.org/10.1152/jappl.2000.88.6.2219
  221. 221.
    Wong HS, Dighe PA, Mezera V, Monternier PA, Brand MD (2017) Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions. J Biol Chem 292:16804–16809Google Scholar
  222. 222.
    Wu H, Xing K, Lou MF (2010) Glutaredoxin 2 prevents H2O2-induced cell apoptosis by protecting complex I activity in the mitochondria. Biochim Biophys Acta Bioenerg.  https://doi.org/10.1016/j.bbabio.2010.06.003
  223. 223.
    Wu Q, Xia SX, Li QQ, Gao Y, Shen X, Ma L, Zhang MY, Wang T, Li YS, Wang ZF, Luo CL, Tao LY (2016) Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. Brain Res.  https://doi.org/10.1016/j.brainres.2015.11.016
  224. 224.
    Wu Y, Viana M, Thirumangalathu S, Loeken MR (2012) AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy. Diabetologia.  https://doi.org/10.1007/s00125-011-2326-y
  225. 225.
    Yeon J-Y, Min S-H, Park H-J, Kim J-W, Lee Y-H, Park S-Y, Jeong P-S, Park H, Lee D-S, Kim S-U, Chang K-T, Koo D-B (2015) Mdivi-1, mitochondrial fission inhibitor, impairs developmental competence and mitochondrial function of embryos and cells in pigs. J Reprod Dev.  https://doi.org/10.1262/jrd.2014-070
  226. 226.
    Youle RJ, Van Der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science (80-. ) 337:1062–1065Google Scholar
  227. 227.
    Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol.  https://doi.org/10.1038/nrm3028
  228. 228.
    Yuan H, Gerencser AA, Liot G, Lipton SA, Ellisman M, Perkins GA, Bossy-Wetzel E (2007) Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death Differ.  https://doi.org/10.1038/sj.cdd.4402046
  229. 229.
    Zechner C, Lai L, Zechner JF, Geng T, Yan Z, Rumsey JW, Collia D, Chen Z, Wozniak DF, Leone TC, Kelly DP (2010) Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab.  https://doi.org/10.1016/j.cmet.2010.11.008
  230. 230.
    Zhang L, He Z, Zhang Q, Wu Y, Yang X, Niu W, Hu Y, Jia J (2014) Exercise pretreatment promotes mitochondrial dynamic protein OPA1 expression after cerebral ischemia in rats. Int J Mol Sci.  https://doi.org/10.3390/ijms15034453
  231. 231.
    Zhang QJ, Mcmillin SL, Tanner JM, Palionyte M, Abel ED, Symons JD (2009) Endothelial nitric oxide synthase phosphorylation in treadmill-running mice: role of vascular signalling kinases. J Physiol.  https://doi.org/10.1113/jphysiol.2009.172916
  232. 232.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest.  https://doi.org/10.1172/JCI13505
  233. 233.
    Zmijewski JW, Banerjee S, Bae H, Friggeri A, Lazarowski ER, Abraham E (2010) Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem.  https://doi.org/10.1074/jbc.M110.143685
  234. 234.
    Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG IV, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochondrial reactive nitrogen species. J Biol Chem.  https://doi.org/10.1074/jbc.M404421200
  235. 235.
    Zou MH, Shi C, Cohen RA (2002) High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H2receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes.  https://doi.org/10.2337/diabetes.51.1.198
  236. 236.
    Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, De Jonghe P, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battologlu E, Polyakov AV, Timmerman V, Schröder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet.  https://doi.org/10.1038/ng1341

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tomohiro Tanaka
    • 1
    • 2
  • Akiyuki Nishimura
    • 1
    • 3
    • 4
    • 5
  • Kazuhiro Nishiyama
    • 5
  • Takumi Goto
    • 5
  • Takuro Numaga-Tomita
    • 1
    • 3
    • 4
  • Motohiro Nishida
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Division of Cardiocirculatory Signaling, National Institute for Physiological Sciences (NIPS)National Institutes of Natural SciencesAichiJapan
  2. 2.Division of Plasma Biology, Center for Novel Science Initiatives (CNSI)National Institutes of Natural SciencesTokyoJapan
  3. 3.Cardiocirculatory Dynamism Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institute for Physiological Sciences (NIPS)National Institutes of Natural SciencesAichiJapan
  4. 4.SOKENDAI (School of Life Science, The Graduate University for Advanced Studies)AichiJapan
  5. 5.Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan

Personalised recommendations