medigraphic.com

2014, Number 4

<< Back

Rev Mex Anest 2014; 37 (4)

Mitochondria as a therapeutic target

Luna-Ortiz P, Flores-Chávez P, Martínez-Rosas M

Language: Spanish
References: 78
Page: 283-296
PDF size: 335.74 Kb.


ABSTRACT

Mitochondria have an important role in energy production in cells. In addition to their well known roles in oxidative phosphorylation and metabolism, it is now clear that the mitochondria are also central to cell death, neoplasia, cell differentiation, and the innate immune system, for detecting levels of oxygen and hypoxia and calcium homeostasis. These organelles are increasingly being recognized as key elements in many areas of biomedical science. The disruption of any of the functional roles of mitochondria contributes to diseases, so this organelle turns on a potentially important therapeutic target apparently not considered until recently. Mitochondrial dysfunction is often associated with oxidative damage, alterations in calcium homeostasis and defects in the synthesis of ATP or induction of the permeability transition pore. Thus, therapies designed to prevent this type of damage are beneficial in various conditions that may even seem unrelated. In this review we highlight the biological properties that make mitochondria determinants of health and disease. Besides the possible pharmacological strategies being developed and even some that are already applied in humans to influence mitochondrial dysfunction and restore function are described. Mitochondria as a therapeutic target would result in what it has been called mitochondrial pharmacology and represent a promising discipline with enormous potential for new therapeutic approaches with implications in many diseases.


REFERENCES

  1. Wallace DC, et al. Mitochondrial energetics and therapeutics. Annu Rev Pathol. 2010;5:297-348.

  2. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-137.

  3. Murphy E, et al. Mitochondria: from basic biology to cardiovascular disease. J Mol Cell Cardiol. 2009;46:765-766.

  4. Smith RAJ, et al. Mitochondria-targeted small molecule therapeutics and probes. Antioxid Redox Signal. 2011;15:3021-3038.

  5. Mammucari C, et al. Molecules and roles of mitochondrial calcium signaling. BioFactors 2011;37: 219-227.

  6. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1-13.

  7. Arnoult D, et al. Mitochondria in innate immunity. EMBO Rep. 2011;12:901-910.

  8. Tormos KV, et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 2011;14:537-544.

  9. Calvo SE, Mootha VK. The mitochondrial proteome and human disease. Annu Rev Genomics Hum. Genet. 2010;11:25-44.

  10. Green DR, et al. Mitochondria and the autophagyinflammation-cell death axis in organismal aging. Science. 2011;333:1109-1112.

  11. Narendra DP, Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid Redox Signal. 2011;14:1929-1938.

  12. Kim I, et al. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462:245-253.

  13. Ahmed W, Ziouzenkova O, Brown J, et al. PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? J of Inter Med. 2007;262:184-198

  14. Ventura-Clapier R, et al. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008;79:208-217.

  15. Goto Y, et al. A mutation in the tRNALeu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348:651-653.

  16. Erickson RP. Leber’s optic atrophy, a possible example of maternal inheritance. Am J Hum Genet. 1972;24(3):348-349.

  17. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): disease entity or a syndrome? Light-and electron-microscopic studies of two cases and review of literature. Journal of the neurological sciences. 1980;47.

  18. Smeitink J, et al. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2: 342-352.

  19. Leonard JV, Schapira AH. Mitochondrial respiratory chain disorders II: neurodegenerative disorders and nuclear gene defects. Lancet. 2000;355:389-394.

  20. Angelini C, et al. Mitochondrial disorders of the nuclear genome. Acta Myol. 2009;28:16-23.

  21. Saada A, et al. Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Am J Hum Genet. 2009;84:718-727.

  22. McKenzie M, Ryan MT. Assembly factors of human mitochondrial complex I and their defects in disease. IUBMB Life. 2010;62:497-502.

  23. Halestrap A. Biochemistry: a pore way to die. Nature. 2005;434:578-579.

  24. Murphy MP. Mitochondria -a neglected drug target. Curr Opin Invest Drugs. 2009;10:1022-1024.

  25. Cree LM, et al. The inheritance of pathogenic mitochondrial DNA mutations. Biochim Biophys Acta. 2009;1792:1097-1102.

  26. Hassani A, et al. Mitochondrial myopathies: developments in treatment. Curr Opin Neurol. 2010;23:459-465.

  27. Kyriakouli DS, et al. Progress and prospects: gene therapy for mitochondrial DNA disease. Gene Ther. 2008;15:1017-1023.

  28. Rasola A, Bernardi P. Mitochondrial permeability transition in Ca2+ dependent apoptosis and necrosis. Cell Calcium. 2011;50:222-233.

  29. Murphy MP, Smith RAJ. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol. 2007;47:629-656.

  30. Szeto HH, Schiller PW. Novel therapies targeting inner mitochondrial membrane from discovery to clinical development. Pharm. Res. 2011; 8:2669-2679.

  31. Porteous CM, et al. Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: implications for mitochondria-specific therapies and probes. Biochim Biophys Acta. 2010;1800:1009-1017.

  32. Rodriguez-Cuenca S, et al. Consequences of long-term oral administration of the mitochondria-targeted antioxidant MitoQ to wild-type mice. Free Radic Biol Med. 2010;48:161-172.

  33. Teicher BA, et al. Efficacy of Pt (Rh-123) 2 as a radiosensitizer with fractionated X rays. Int J Radiat Oncol Biol Phys. 1987;13:1217-1224.

  34. Yousif LF, et al. Targeting mitochondria with organelle-specific compounds: strategies and applications. ChemBiochem. 2009;10:1939-1950.

  35. Yousif LF, et al. Mitochondria-penetrating peptides: sequence effects and model cargo transport. ChemBiochem. 2009;10:2081-2088.

  36. Ripcke J, et al. Small-molecule targeting of the mitochondrial compartment with an endogenously cleaved reversible tag. ChemBiochem. 2009;10:1689-1696.

  37. Prime TA, et al. A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury. Proc Natl Acad Sci. 2009;106:10764-10769.

  38. Chalmers S, et al. Selective uncoupling of individual mitochondria within a cell using a mitochondria-targeted photoactivated protonophore. J Am Chem Soc. 2012;134:758-761.

  39. Rotenberg SA, et al. A self-assembling protein kinase C inhibitor. Proc Natl Acad Sci. 1991;88:2490-2494.

  40. Pereira MP, Kelley SO. Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells. J Am Chem Soc. 2011;133:3260-3263.

  41. Snow BJ, et al. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease modifying therapy in Parkinson’s disease. Mov Disord. 2010;25:1670-1674.

  42. Gane EJ, et al. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int. 2010;30:1019-1026.

  43. Ghosh A, et al. Neuroprotection by a mitochondria-targeted drug in a Parkinson’s disease model. Free Radic Biol Med. 2010;49:1674-1684.

  44. Skulachev VP, et al. An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta. 2009;1787:437-461.

  45. Mitchell T, et al. The mitochondria-targeted antioxidant mitoquinone protects against cold storage injury of renal tubular cells and rat kidneys. J Pharmacol Exp Ther. 2011;336:682-692.

  46. McManus MJ, et al. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci. 2011;31:15703-15715.

  47. Chouchani ET, et al. Identification of S-nitrosated mitochondrial proteins by S-nitrosothiol difference in gel electrophoresis (SNO-DIGE): implications for the regulation of mitochondrial function by reversible S-nitrosation. Biochem J. 2010;430:49-59.

  48. Li Y, et al. Effect of cyclosporin A on the pharmacokinetics of mitoquinone (MitoQ10), a mitochondria-targeted antioxidant in rat. Asian J Pharm Sci. 2010;5:106-113.

  49. Bjelakovic G, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2008; 3. CD007176.

  50. Smith RAJ, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci. 2010;1201:96-103.

  51. Millard M, et al. Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity. Plos ONE. 2010;5.

  52. Fulda S, et al. Targeting mitochondria for cancer therapy. Nat Rev Drug Dis. 2010;9:447-464.

  53. Piot C, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008;359:473-481.

  54. Merlini L, Bernardi P. Therapy of collagen VI-related myopathies (Bethlem and Ullrich). Neurotherapeutics. 2008;5:613-618.

  55. Merlini L, et al. Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology. 2008;71:1245-1253.

  56. Irwin WA, et al. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet. 2003;35:367-371.

  57. Hohenester BR. A therapy for myopathy caused by collagen VI mutations? Matrix Biol. 2007;26: 145.

  58. Merlini L, et al. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies. Proc Natl Acad Sci. 2008;105:5225-5229.

  59. Hansson MJ, et al. The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr. 2004;36:407-413.

  60. Cassidy-Stone A, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14:193-204.

  61. Ong SB, et al. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation. 2010;121:2012-2022.

  62. Harper JA, et al. Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev. 2001;2:255-265.

  63. Severin FF, et al. Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc Natl Acad Sci. 2010;107:663-668.

  64. Lou PH, et al. Mitochondrial uncouplers with an extraordinary dynamic range. Biochem J. 2007;407:129-140.

  65. Sanz A, et al. Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc Natl Acad Sci. 2010;107:9105-9110.

  66. Fernandez-Ayala DJ, et al. Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation. Cell Metab. 2009;9:449-460.

  67. Atamna H, Kumar R. Protective role of methylene blue in Alzheimer’s disease via mitochondria and cytochrome c oxidase. J Alzheimer’s Dis. 2010;20:S439-S452.

  68. Haefeli RH, et al. NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS ONE. 2011;6:e17963.

  69. Eleff S, et al. 31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle. Proc Natl Acad Sci. 1984;81:3529-3533.

  70. Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S-890S.

  71. Wenz T, et al. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008;8:249-256.

  72. Sundaresan NR et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest. 2009;119:2758-2771.

  73. Milne JC, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450:712-716.

  74. Westphal CH, et al. A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci. 2007;32:555-560.

  75. Guarente L. Mitochondria - a nexus for aging, calorie restriction, and sirtuins? Cell. 2008;132:171-176.

  76. Park SJ, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012;148:421-433.

  77. Hadzimichalis NM, Baliga SS, Golfetti R, Jaques KM, Firestein BL, Merrill GF. Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway. Am J Physiol Heart Circ Physiol. 2007; 293:H3348-3355.

  78. Chiari P, Angoulvant D, Mewton N, Desebbe O, Obadia JF, Robin J, Farhat F, Jegaden O, Bastien O, Lehot JJ, Ovize M. Cyclosporine protects the heart during aortic valve surgery. Anesthesiology. 2014; 121: 232-238.




2020     |     www.medigraphic.com