Novel targets for mitochondrial medicine

Science Translational Medicine

Volumn 8, Issue 326, 2016, Pages

  Wang, Wang ^a   Karamanlidis, Georgios ^b   Tian, Rong ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; CALCIUM ION; REACTIVE OXYGEN METABOLITE; CALCIUM; MITOCHONDRIAL PROTEIN;

ALZHEIMER DISEASE; CALCIUM TRANSPORT; CELL ORGANELLE; CELL STRESS; DIABETES MELLITUS; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENVIRONMENTAL STRESS; HUMAN; METABOLIC DISORDER; MITOCHONDRIAL REPLACEMENT THERAPY; MITOCHONDRION; NEOPLASM; OBESITY; OXIDATIVE PHOSPHORYLATION; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN MODIFICATION; REVIEW; MEDICINE; METABOLISM; MITOCHONDRIAL DYNAMICS; MOLECULARLY TARGETED THERAPY;

CALCIUM; HUMANS; MEDICINE; MITOCHONDRIA; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL PROTEINS; MOLECULAR TARGETED THERAPY;

EID: 84975748778     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aac7410     Document Type: Review

References (88)

1. A. M. Walters, G. A. Porter Jr., P. S. Brookes, Mitochondria as a drug target in ischemic heart disease and cardiomyopathy. Circ. Res. 111, 1222-1236 (2012).
2. Y. Ishimoto, R. Inagi, Mitochondria: A therapeutic target in acute kidney injury. Nephrol. Dial. Transplant., gfv317 (2015).
3. J. Liu, L.-N. Wang, Mitochondrial enhancement for neurodegenerative movement disorders: A systematic review of trials involving creatine, coenzyme Q10, idebenone and mitoquinone. CNS Drugs 28, 63-68 (2014).
4. E. C. Ienco, A. LoGerfo, C. Carlesi, D. Orsucci, G. Ricci, M. Mancuso, G. Siciliano, Oxidative stress treatment for clinical trials in neurodegenerative diseases. J. Alzheimers Dis. 24 (Suppl. 2), 111-126 (2011).
5. G. F. Kelso, C. M. Porteous, C. V. Coulter, G. Hughes, W. K. Porteous, E. C. Ledgerwood, R. A. J. Smith, M. P. Murphy, Selective targeting of a redox-active ubiquinone to mitochondria within cells: Antioxidant and antiapoptotic properties. J. Biol. Chem. 276, 4588-4596 (2001).
6. M.-C. Frantz, P. Wipf, Mitochondria as a target in treatment. Environ. Mol. Mutagen. 51, 462-475 (2010).
7. G. M. Enns, S. L. Kinsman, S. L. Perlman, K. M. Spicer, J. E. Abdenur, B. H. Cohen, A. Amagata, A. Barnes, V. Kheifets, W. D. Shrader, M. Thoolen, F. Blankenberg, G. Miller, Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol. Genet. Metab. 105, 91-102 (2012).
8. W. D. Shrader, A. Amagata, A. Barnes, G. M. Enns, A. Hinman, O. Jankowski, V. Kheifets, R. Komatsuzaki, E. Lee, P. Mollard, K. Murase, A. A. Sadun, M. Thoolen, K. Wesson, G. Miller, a-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorg. Med. Chem. Lett. 21, 3693-3698 (2011).
9. S. E. Weinberg, N. S. Chandel, Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9-15 (2015).
10. O. C. Ubah, H. M. Wallace, Cancer therapy: Targeting mitochondria and other sub-cellular organelles. Curr. Pharm. Des. 20, 201-222 (2014).
11. S. Patergnani, S. Missiroli, S. Marchi, C. Giorgi, Mitochondria-associated endoplasmic reticulum membranes microenvironment: Targeting autophagic and apoptotic pathways in cancer therapy. Front. Oncol. 5, 173 (2015).
12. S. Fulda, L. Galluzzi, G. Kroemer, Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov. 9, 447-464 (2010).
13. L. Craven, H. A. Tuppen, G. D. Greggains, S. J. Harbottle, J. L. Murphy, L. M. Cree, A. P. Murdoch, P. F. Chinnery, R. W. Taylor, R. N. Lightowlers, M. Herbert, D. M. Turnbull, Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 465, 82-85 (2010).
14. D. Paull, V. Emmanuele, K. A. Weiss, N. Treff, L. Stewart, H. Hua, M. Zimmer, D. J. Kahler, R. S. Goland, S. A. Noggle, R. Prosser, M. Hirano, M. V. Sauer, D. Egli, Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature 493, 632-637 (2013).
15. M. Tachibana, P. Amato, M. Sparman, J. Woodward, D. M. Sanchis, H. Ma, N. M. Gutierrez, R. Tippner-Hedges, E. Kang, H.-S. Lee, C. Ramsey, K. Masterson, D. Battaglia, D. Lee, D. Wu, J. Jensen, P. Patton, S. Gokhale, R. Stouffer, S. Mitalipov, Towards germline gene therapy of inherited mitochondrial diseases. Nature 493, 627-631 (2013).
16. I. Scott, B. R. Webster, J. H. Li, M. N. Sack, Identification of a molecular component of the mitochondrial acetyltransferase programme: A novel role for GCN5L1. Biochem. J. 443, 655-661 (2012).
17. J. Baeza, M. J. Smallegan, J. M. Denu, Site-specific reactivity of nonenzymatic lysine acetylation. ACS Chem. Biol. 10, 122-128 (2015).
18. M. D. Hirschey, Y. Zhao, Metabolic regulation by lysine malonylation, succinylation and glutarylation. Mol. Cell. Proteomics 14, 2308-2315 (2015).
19. M. D. Hirschey, T. Shimazu, E. Jing, C. A. Grueter, A. M. Collins, B. Aouizerat, A. Stančáková, E. Goetzman, M. M. Lam, B. Schwer, R. D. Stevens, M. J.Muehlbauer, S. Kakar, N. M. Bass, J. Kuusisto, M. Laakso, F. W. Alt, C. B. Newgard, R. V. Farese Jr., C. R. Kahn, E. Verdin, SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 44, 177-190 (2011).
20. N. R. Sundaresan, M. Gupta, G. Kim, S. B. Rajamohan, A. Isbatan, M. P. Gupta, Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758-2771 (2009).
21. A. V. Hafner, J. Dai, A. P. Gomes, C.-Y. Xiao, C. M. Palmeira, A. Rosenzweig, D. A. Sinclair, Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging 2, 914-923 (2010).
22. G. Karamanlidis, C. F. Lee, L. Garcia-Menendez, S. C. Kolwicz Jr., W. Suthammarak, G. Gong, M. M. Sedensky, P. G. Morgan, W. Wang, R. Tian, Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 18, 239-250 (2013).
23. O. A. Alrob, S. Sankaralingam, C. Ma, C. S. Wagg, N. Fillmore, J. S. Jaswal, M. N. Sack, R. Lehner, M. P. Gupta, E. D. Michelakis, R. S. Padwal, D. E. Johnstone, A. M. Sharma, G. D. Lopaschuk, Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling. Cardiovasc. Res. 103, 485-497 (2014).
24. C. Cantó, R. H. Houtkooper, E. Pirinen, D. Y. Youn, M. H. Oosterveer, Y. Cen, P. J. Fernandez-Marcos, H. Yamamoto, P. A. Andreux, P. Cettour-Rose, K. Gademann, C. Rinsch, K. Schoonjans, A. A. Sauve, J. Auwerx, The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838-847 (2012).
25. G. R. Wagner, P. M. Pride, C. M. Babbey, R. M. Payne, Friedreich's ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase. Hum. Mol. Genet. 21, 2688-2697 (2012).
26. J.W. Elrod, R. Wong, S. Mishra, R. J. Vagnozzi, B. Sakthievel, S. A. Goonasekera, J. Karch, S. Gabel, J. Farber, T. Force, J. H. Brown, E. Murphy, J. D. Molkentin, Cyclophilin D controls mitochondrial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice. J. Clin. Invest. 120, 3680-3687 (2010).
27. R. J. Colman, R. M. Anderson, S. C. Johnson, E. K. Kastman, K. J. Kosmatka, T. M. Beasley, D. B. Allison, C. Cruzen, H. A. Simmons, J. W. Kemnitz, R. Weindruch, Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201-204 (2009).
28. X. Qiu, K. Brown, M. D. Hirschey, E. Verdin, D. Chen, Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12, 662-667 (2010).
29. L. Guarente, Calorie restriction and sirtuins revisited. Genes Dev. 27, 2072-2085 (2013).
30. J. Yoshino, K. F. Mills, M. J. Yoon, S.-I. Imai, Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528-536 (2011).
31. G. Wang, T. Han, D. Nijhawan, P. Theodoropoulos, J. Naidoo, S. Yadavalli, H. Mirzaei, A. A. Pieper, J. M. Ready, S. L. McKnight, P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158, 1324-1334 (2014).
32. A. P. Gomes, N. L. Price, A. J. Y. Ling, J. J. Moslehi, M. K. Montgomery, L. Rajman, J. P. White, J. S. Teodoro, C. D. Wrann, B. P. Hubbard, E. M. Mercken, C. M. Palmeira, R. de Cabo, A. P. Rolo, N. Turner, E. L. Bell, D. A. Sinclair, Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624-1638 (2013).
33. T. Calì, D. Ottolini, M. Brini, Mitochondrial Ca2+ and neurodegeneration. Cell Calcium 52, 73-85 (2012).
34. G. S. B. Williams, L. Boyman, W. J. Lederer, Mitochondrial calcium and the regulation of metabolism in the heart. J. Mol. Cell. Cardiol. 78, 35-45 (2015).
35. D. De Stefani, A. Raffaello, E. Teardo, I. Szabò, R. Rizzuto, A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336-340 (2011).
36. J. M. Baughman, F. Perocchi, H. S. Girgis, M. Plovanich, C. A. Belcher-Timme, Y. Sancak, X. R. Bao, L. Strittmatter, O. Goldberger, R. L. Bogorad, V. Koteliansky, V. K. Mootha, Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341-345 (2011).
37. D. De Stefani, M. Patron, R. Rizzuto, Structure and function of the mitochondrial calcium uniporter complex. Biochim. Biophys. Acta 1853, 2006-2011 (2015).
38. G. de J. García-Rivas, K. Carvajal, F. Correa, C. Zazueta, Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br. J. Pharmacol. 149, 829-837 (2006).
39. E. Murphy, C. Steenbergen, Mechanisms underlying acute protection from cardiac ischemiareperfusion injury. Physiol. Rev. 88, 581-609 (2008).
40. K. Shintani-Ishida, M. Inui, K.-i. Yoshida, Ischemia-reperfusion induces myocardial infarction through mitochondrial Ca2+ overload. J. Mol. Cell. Cardiol. 53, 233-239 (2012).
41. X. Pan, J. Liu, T. Nguyen, C. Liu, J. Sun, Y. Teng, M. M. Fergusson, I. I. Rovira, M. Allen, D. A. Springer, A. M. Aponte, M. Gucek, R. S. Balaban, E. Murphy, T. Finkel, The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat. Cell. Biol. 15, 1464-1472 (2013).
42. T. S. Luongo, J. P. Lambert, A. Yuan, X. Zhang, P. Gross, J. Song, S. Shanmughapriya, E. Gao, M. Jain, S. R. Houser, W. J. Koch, J. Y. Cheung, M. Madesh, J. W. Elrod, The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. Cell. Rep. 12, 23-34 (2015).
43. J. Q. Kwong, X. Lu, R. N. Correll, J. A. Schwanekamp, R. J. Vagnozzi, M. A. Sargent, A. J. York, J. Zhang, D. M. Bers, J. D. Molkentin, The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell. Rep. 12, 15-22 (2015).
44. C. P. Baines, R. A. Kaiser, N. H. Purcell, N. S. Blair, H. Osinska, M. A. Hambleton, E. W. Brunskill, M. R. Sayen, R. A. Gottlieb, G. W. Dorn II, J. Robbins, J. D. Molkentin, Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658-662 (2005).
45. C. Piot, P. Croisille, P. Staat, H. Thibault, G. Rioufol, N. Mewton, R. Elbelghiti, T. T. Cung, E. Bonnefoy, D. Angoulvant, C. Macia, F. Raczka, C. Sportouch, G. Gahide, G. Finet, X. André-Fouët, D. Revel, G. Kirkorian, J.-P. Monassier, G. Derumeaux, M. Ovize, Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N. Engl. J. Med. 359, 473-481 (2008).
46. T.-T. Cung, O. Morel, G. Cayla, G. Rioufol, D. Garcia-Dorado, D. Angoulvant, E. Bonnefoy-Cudraz, P. Guérin, M. Elbaz, N. Delarche, P. Coste, G. Vanzetto, M. Metge, J.-F. Aupetit, B. Jouve, P. Motreff, C. Tron, J.-N. Labeque, P. G. Steg, Y. Cottin, G. Range, J. Clerc, M. J. Claeys, P. Coussement, F. Prunier, F. Moulin, O. Roth, L. Belle, P. Dubois, P. Barragan, M. Gilard, C. Piot, P. Colin, F. De Poli, M.-C. Morice, O. Ider, J.-L. Dubois-Randé, T. Unterseeh, H. Le Breton, T. Béard, D. Blanchard, G. Grollier, V. Malquarti, P. Staat, A. Sudre, E. Elmer, M. J. Hansson, C. Bergerot, I. Boussaha, C. Jossan, G. Derumeaux, N. Mewton, M. Ovize, Cyclosporine before PCI in patients with acute myocardial infarction. N. Engl. J. Med. 373, 1021-1031 (2015).
47. W. Wang, H. Fang, L. Groom, A. Cheng, W. Zhang, J. Liu, X. Wang, K. Li, P. Han, M. Zheng, J. Yin, W. Wang, M. P. Mattson, J. P. Kao, E. G. Lakatta, S.-S. Sheu, K. Ouyang, J. Chen, R. T. Dirksen, H. Cheng, Superoxide flashes in single mitochondria. Cell 134, 279-290 (2008).
48. K. N. Alavian, G. Beutner, E. Lazrove, S. Sacchetti, H.-A. Park, P. Licznerski, H. Li, P. Nabili, K. Hockensmith, M. Graham, G. A. Porter Jr., E. A. Jonas, An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc. Natl. Acad. Sci. U.S.A. 111, 10580-10585 (2014).
49. V. Giorgio, S. von Stockum, M. Antoniel, A. Fabbro, F. Fogolari, M. Forte, G. D. Glick, V. Petronilli, M. Zoratti, I. Szabó, G. Lippe, P. Bernardi, Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc. Natl. Acad. Sci. U.S.A. 110, 5887-5892 (2013).
50. J. R. Friedman, J. Nunnari, Mitochondrial form and function. Nature 505, 335-343 (2014).
51. A. R. Hall, N. Burke, R. K. Dongworth, D. J. Hausenloy, Mitochondrial fusion and fission proteins: Novel therapeutic targets for combating cardiovascular disease. Br. J. Pharmacol. 171, 1890-1906 (2014).
52. D. C. Chan, Fusion and fission: Interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46, 265-287 (2012).
53. G. W. Dorn II, Mitochondrial dynamism and heart disease: Changing shape and shaping change. EMBO Mol. Med. 7, 865-877 (2015).
54. A. Cassidy-Stone, J. E. Chipuk, E. Ingerman, C. Song, C. Yoo, T. Kuwana, M. J. Kurth, J. T. Shaw, J. E. Hinshaw, D. R. Green, J. Nunnari, Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev. Cell 14, 193-204 (2008).
55. X. Qi, N. Qvit, Y.-C. Su, D. Mochly-Rosen, A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J. Cell Sci. 126, 789-802 (2013).
56. S.-B. Ong, S. Subrayan, S. Y. Lim, D. M. Yellon, S. M. Davidson, D. J. Hausenloy, Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121, 2012-2022 (2010).
57. W. Yue, Z. Chen, H. Liu, C. Yan, M. Chen, D. Feng, H. Wu, L. Du, Y. Wang, J. Liu, X. Huang, L. Xia, L. Liu, X. Wang, H. Jin, J. Wang, Z. Song, X. Hao, Q. Chen, A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res. 24, 482-496 (2014).
58. Y. Ikeda, A. Shirakabe, Y. Maejima, P. Zhai, S. Sciarretta, J. Toli, M. Nomura, K. Mihara, K. Egashira, M. Ohishi, M. Abdellatif, J. Sadoshima, Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ. Res. 116, 264-278 (2015).
59. Y. Kageyama, M. Hoshijima, K. Seo, D. Bedja, P. Sysa-Shah, S. A. Andrabi, W. Chen, A. Höke, V. L. Dawson, T. M. Dawson, K. Gabrielson, D. A. Kass, M. Iijima, H. Sesaki, Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J. 33, 2798-2813 (2014).
60. M. Song, K. Mihara, Y. Chen, L. Scorrano, G. W. Dorn II, Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab. 21, 273-285 (2015).
61. G. W. Dorn II, M. Song, K. Walsh, Functional implications of mitofusin 2-mediated mitochondrial- SR tethering. J. Mol. Cell. Cardiol. 78, 123-128 (2015).
62. S. Cogliati, C. Frezza, M. E. Soriano, T. Varanita, R. Quintana-Cabrera, M. Corrado, S. Cipolat, V. Costa, A. Casarin, L. C. Gomes, E. Perales-Clemente, L. Salviati, P. Fernandez-Silva, J. A. Enriquez, L. Scorrano, Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155, 160-171 (2013).
63. T. Varanita, M. E. Soriano, V. Romanello, T. Zaglia, R. Quintana-Cabrera, M. Semenzato, R. Menabò, V. Costa, G. Civiletto, P. Pesce, C. Viscomi, M. Zeviani, F. Di Lisa, M.Mongillo, M. Sandri, L. Scorrano, The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab. 21, 834-844 (2015).
64. G. Civiletto, T. Varanita, R. Cerutti, T. Gorletta, S. Barbaro, S. Marchet, C. Lamperti, C. Viscomi, L. Scorrano, M. Zeviani, Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models. Cell Metab. 21, 845-854 (2015).
65. S. Montessuit, S. P. Somasekharan, O. Terrones, S. Lucken-Ardjomande, S. Herzig, R. Schwarzenbacher, D. J. Manstein, E. Bossy-Wetzel, G. Basañez, P. Meda, J.-C. Martinou, Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142, 889-901 (2010).
66. O. M. de Brito, L. Scorrano, Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605-610 (2008).
67. Y. Chen, G. Csordás, C. Jowdy, T. G. Schneider, N. Csordás, W. Wang, Y. Liu, M. Kohlhaas, M. Meiser, S. Bergem, J. M. Nerbonne, G. W. Dorn II, C. Maack, Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. Circ. Res. 111, 863-875 (2012).
68. A. Sood, D. V. Jeyaraju, J. Prudent, A. Caron, P. Lemieux, H. M. McBride, M. Laplante, K. Tóth, L. Pellegrini, A Mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver. Proc. Natl. Acad. Sci. U.S.A. 111, 16017-16022 (2014).
69. A. P. Arruda, B. M. Pers, G. Parlakgül, E. Güney, K. Inouye, G. S. Hotamisligil, Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 20, 1427-1435 (2014).
70. F. Korobova, V. Ramabhadran, H. N. Higgs, An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339, 464-467 (2013).
71. V. Eisner, G. Csordás, G. Hajnóczky, Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle-pivotal roles in Ca2+ and reactive oxygen species signaling. J. Cell Sci. 126, 2965-2978 (2013).
72. G. Csordás, P. Várnai, T. Golenár, S. Roy, G. Purkins, T. G. Schneider, T. Balla, G. Hajnóczky, Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol. Cell 39, 121-132 (2010).
73. L.-S. Song, E. A. Sobie, S. McCulle, W. J. Lederer, C. W. Balke, H. Cheng, Orphaned ryanodine receptors in the failing heart. Proc. Natl. Acad. Sci. U.S.A. 103, 4305-4310 (2006).
74. G. M. Buyse, T. Voit, U. Schara, C. S. M. Straathof, M. G. D'Angelo, G. Bernert, J.-M. Cuisset, R. S. Finkel, N. Goemans, C. M. McDonald, C. Rummey, T. Meier; DELOS Study Group, Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): A double-blind randomised placebo-controlled phase 3 trial. Lancet 385, 1748-1757 (2015).
75. K. Tsujita, H. Shimomura, K. Kaikita, H. Kawano, J. Hokamaki, Y. Nagayoshi, T. Yamashita, M. Fukuda, Y. Nakamura, T. Sakamoto, M. Yoshimura, H. Ogawa, Long-term efficacy of edaravone in patients with acute myocardial infarction. Circ. J. 70, 832-837 (2006).
76. K. Abe, Y. Itoyama, G. Sobue, S. Tsuji, M. Aoki, M. Doyu, C. Hamada, K. Kondo, T. Yoneoka, M. Akimoto, H. Yoshino; Edaravone ALS Study Group, Confirmatory double-blind, parallelgroup, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 610-617 (2014).
77. Parkinson Study Group QE3 Investigators, M. F. Beal, D. Oakes, I. Shoulson, C. Henchcliffe, W. R. Galpern, R. Haas, J. L. Juncos, J. G. Nutt, T. S. Voss, B. Ravina, C. M. Shults, K. Helles, V. Snively, M. F. Lew, B. Griebner, A. Watts, S. Gao, E. Pourcher, L. Bond, K. Kompoliti, P. Agarwal, C. Sia, M. Jog, L. Cole, M. Sultana, R. Kurlan, I. Richard, C. Deeley, C. H. Waters, A. Figueroa, A. Arkun, M. Brodsky, W. G. Ondo, C. B. Hunter, J. Jimenez-Shahed, A. Palao, J. M. Miyasaki, J. So, J. Tetrud, L. Reys, K. Smith, C. Singer, A. Blenke, D. S. Russell, C. Cotto, J. H. Friedman, M. Lannon, L. Zhang, E. Drasby, R. Kumar, T. Subramanian, D. S. Ford, D. A. Grimes, D. Cote, J. Conway, A. D. Siderowf, M. L. Evatt, B. Sommerfeld, A. N. Lieberman, M. S. Okun, R. L. Rodriguez, S. Merritt, C. L. Swartz, W. R. Martin, P. King, N. Stover, S. Guthrie, R. L. Watts, A. Ahmed, H. H. Fernandez, A. Winters, Z. Mari, T. M. Dawson, B. Dunlop, A. S. Feigin, B. Shannon, M. J. Nirenberg, M. Ogg, S. A. Ellias, C. A. Thomas, K. Frei, I. Bodis-Wollner, S. Glazman, T. Mayer, R. A. Hauser, R. Pahwa, A. Langhammer, R. Ranawaya, L. Derwent, K. D. Sethi, B. Farrow, R. Prakash, I. Litvan, A. Robinson, A. Sahay, M. Gartner, V. K. Hinson, S. Markind, M. Pelikan, J. S. Perlmutter, J. Hartlein, E. Molho, S. Evans, C. H. Adler, A. Duffy, M. Lind, L. Elmer, K. Davis, J. Spears, S. Wilson, M. A. Leehey, N. Hermanowicz, S. Niswonger, H. A. Shill, S. Obradov, A. Rajput, M. Cowper, S. Lessig, D. Song, D. Fontaine, C. Zadikoff, K. Williams, K. A. Blindauer, J. Bergholte, C. S. Propsom, M. A. Stacy, J. Field D. K. Simon, L. Kraics, A. Silver, J. T. Boyd, R. W. Hamill, C. Ingvoldstad, J. Young, K. Thomas, S. K. Kostyk, J. Wojcieszek, R. F. Pfeiffer, M. Panisset, M. Beland, S. G. Reich, M. Cines, N. Zappala, J. Rivest, R. Zweig, L. P. Lumina, C. L. Hilliard, S. Grill, M. Kellermann, P. Tuite, S. Rolandelli, U. J. Kang, J. Rao, M. M. Cook, L. Severt, K. Boyar, A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: No evidence of benefit. JAMA Neurol. 71, 543-552 (2014).
78. H. Makimura, T. L. Stanley, C. Suresh, A. Luisa De Sousa-Coelho, W. R. Frontera, S. Syu, L. R. Braun, S. E. Looby, M. N. Feldpausch, M. Torriani, H. Lee, M.-E. Patti, S. K. Grinspoon, Metabolic effects of long-term reduction in free fatty acids with acipimox in obesity: A randomized trial. J. Clin. Endocrinol. Metab., 10.1210/jc.2015-3696 (2015).
79. M. F. Newman, T. B. Ferguson, J. A. White, G. Ambrosio, J. Koglin, N. A. Nussmeier, R. G. Pearl, B. Pitt, A. S. Wechsler, R. D. Weisel, T. L. Reece, A. Lira, R. A. Harrington; RED-CABG Steering Committee and Investigators, Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: The RED-CABG randomized controlled trial. JAMA 308, 157-164 (2012).
80. I. Bezprozvanny, The rise and fall of Dimebon. Drug News Perspect. 23, 518-523 (2010).
81. D. Atar, H. Arheden, A. Berdeaux, J.-L. Bonnet, M. Carlsson, P. Clemmensen, V. Cuvier, N. Danchin, J.-L. Dubois-Randé, H. Engblom, D. Erlinge, H. Firat, S. Halvorsen, H. S. Hansen, W. Hauke, E. Heiberg, S. Koul, A.-I. Larsen, P. Le Corvoisier, J. E. Nordrehaug, F. Paganelli, R. M. Pruss, H. Rousseau, S. Schaller, G. Sonou, V. Tuseth, J. Veys, E. Vicaut, S. E. Jensen, Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur. Heart J. 36, 112-119 (2015).
82. V. B. Pillai, S. Samant, N. R. Sundaresan, H. Raghuraman, G. Kim, M. Y. Bonner, J. L. Arbiser, D. I. Walker, D. P. Jones, D. Gius, M. P. Gupta, Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat. Commun. 6, 6656 (2015).
83. L. Argaud, O. Gateau-Roesch, D. Muntean, L. Chalabreysse, J. Loufouat, D. Robert, M. Ovize, Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J. Mol. Cell. Cardiol. 38, 367-374 (2005).
84. D. J. Hausenloy, M. R. Duchen, D. M. Yellon, Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc. Res. 60, 617-625 (2003).
85. L. Gomez, H. Thibault, A. Gharib, J.-M. Dumont, G. Vuagniaux, P. Scalfaro, G. Derumeaux, M. Ovize, Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am. J. Physiol. Heart Circ. Physiol. 293, H1654-H1661 (2007).
86. A. Linkermann, J. H. Bräsen, M. Darding, M. K. Jin, A. B. Sanz, J.-O. Heller, F. De Zen, R. Weinlich, A. Ortiz, H. Walczak, J. M. Weinberg, D. R. Green, U. Kunzendorf, S. Krautwald, Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc. Natl. Acad. Sci. U.S.A. 110, 12024-12029 (2013).
87. P. M. Rappold, M. Cui, J. C. Grima, R. Z. Fan, K. L. de Mesy-Bentley, L. Chen, X. Zhuang, W. J. Bowers, K. Tieu, Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nat. Commun. 5, 5244 (2014).
88. Y.-C. Su, X. Qi, Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum. Mol. Genet. 22, 4545-4561 (2013).