Strategies for treating mitochondrial disorders: An update

Molecular Genetics and Metabolism

Volumn 113, Issue 4, 2014, Pages 253-260

  Scarpelli, Mauro ^a   Todeschini, Alice ^b   Rinaldi, Fabrizio ^b   Rota, Silvia ^b   Padovani, Alessandro ^b   Filosto, Massimiliano ^b  

^a UNIVERSITY OF VERONA   (Italy)

^b SPEDALI CIVILI   (Italy)

Author keywords

Mitochondrial diseases; Mitochondrial DNA; Respiratory chain; Therapy

Indexed keywords

CYCLOSPORIN A; DEOXYRIBONUCLEOSIDE; DEOXYRIBONUCLEOTIDE; DEXPRAMIPEXOLE; ESTROGEN; ESTROGEN RECEPTOR; GLUTATHIONE; IDEBENONE; LACTIC ACID; MITOCHONDRIAL DNA; NICOTINAMIDE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PHOSPHORIBOSYLAMINOIMIDAZOLECARBOXAMIDE FORMYLTRANSFERASE; REACTIVE OXYGEN METABOLITE; RESTRICTION ENDONUCLEASE; RESVERATROL; RETINOL; RIBOFLAVIN; SIRTUIN; THIAMINE; TOXIN; TRANSCRIPTION FACTOR NRF1; TRANSCRIPTION FACTOR NRF2; UBIDECARENONE; VATIQUINONE; VITAMIN B COMPLEX; CALCIUM;

AUTOSOMAL RECESSIVE DISORDER; BIOENERGY; BIOGENESIS; BRAIN DISEASE; CALCIUM HOMEOSTASIS; CITRIC ACID CYCLE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENERGY METABOLISM; ENZYME ACTIVITY; ETHYLMALONIC ENCEPHALOPATHY; GLYCOLYSIS; HETEROPLASMY; HUMAN; LEIGH DISEASE; MELAS SYNDROME; MERRF SYNDROME; METABOLITE; MITOCHONDRIAL DNA DEPLETION SYNDROME; MITOCHONDRIAL GENOME; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL MYOPATHY; MITOCHONDRIAL RESPIRATION; MITOCHONDRION; MNGIE SYNDROME; MODULATION; NEUROPROTECTION; NONHUMAN; RESPIRATORY CHAIN; REVIEW; SUPPLEMENTATION; UPREGULATION; ELECTRON TRANSPORT; GENETICS; HOMEOSTASIS; METABOLISM; MITOCHONDRIAL DISEASES; MITOCHONDRIAL DYNAMICS;

CALCIUM; DNA, MITOCHONDRIAL; ELECTRON TRANSPORT; HOMEOSTASIS; HUMANS; MITOCHONDRIA; MITOCHONDRIAL DISEASES; MITOCHONDRIAL TURNOVER; REACTIVE OXYGEN SPECIES;

EID: 84918782045     PISSN: 10967192     EISSN: 10967206     Source Type: Journal    
DOI: 10.1016/j.ymgme.2014.09.013     Document Type: Review

References (127)

1. Azzu V., Brand M.D. The on-off switches of the mitochondrial uncoupling proteins. Trends Biochem. Sci. 2010, 35:298-307.
2. Cardoso A.R., Queliconi B.B., Kowaltowski A.J. Mitochondrial ion transport pathways: role in metabolic diseases. Biochim. Biophys. Acta 2010, 1797:832-838.
3. West A.P., Shadel G.S., Ghosh S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 2011, 11:389-402.
4. Murphy M.P., Holmgren A., Larsson N.G., Halliwell B., Chang C.J., Kalyanaraman B., Rhee S.G., Thornalley P.J., Partridge L., Gems D., Nyström T., Belousov V., Schumacker P.T., Winterbourn C.C. Unraveling the biological roles of reactive oxygen species. Cell Metab. 2011, 13:361-366.
5. Spencer S.L., Sorger P.K. Measuring and modeling apoptosis in single cells. Cell 2011, 144:926-939.
6. Luft R., Ikkos D., Palmieri G., Ernster L., Afzelius B. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study. J. Clin. Invest. 1962, 41:1776-1804.
7. Schaefer A.M., McFarland R., Blakely E.L., He L., Whittaker R.G., Taylor R.W., Chinnery P.F., Turnbull D.M. Prevalence of mitochondrial DNA disease in adults. Ann. Neurol. 2008, 63:35-39.
8. Koopman W.J., Willems P.H., Smeitink J.A. Monogenic mitochondrial disorders. N. Engl. J. Med. 2012, 366:1132-1141.
9. Schon E.A., DiMauro S., Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 2012, 13:878-889.
10. DiMauro S., Schon E.A. Mitochondrial respiratory-chain diseases. N. Engl. J. Med. 2003, 348:2656-2668.
11. 2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels. Exp. Cell Res. 2007, 313:3076-3089.
12. Trifunovic A., Hansson A., Wredenberg A., Rovio A.T., Dufour E., Khvorostov I., Spelbrink J.N., Wibom R., Jacobs H.T., Larsson N.G. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:17993-17998.
13. Kujoth G.C., Hiona A., Pugh T.D., Someya S., Panzer K., Wohlgemuth S.E., Hofer T., Seo A.Y., Sullivan R., Jobling W.A., Morrow J.D., Van Remmen H., Sedivy J.M., Yamasoba T., Tanokura M., Weindruch R., Leeuwenburgh C., Prolla T.A. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005, 309:481-484.
14. Quinzii C.M., López L.C., Gilkerson R.W., Dorado B., Coku J., Naini A.B., Lagier-Tourenne C., Schuelke M., Salviati L., Carrozzo R., Santorelli F., Rahman S., Tazir M., Koenig M., DiMauro S., Hirano M. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 2010, 24:3733-3743.
15. Loveland B., Wang C.R., Yonekawa H., Hermel E., Lindahl K.F. Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell 1990, 60:971-980.
16. Vafai S.B., Mootha V.K. Mitochondrial disorders as windows into an ancient organelle. Nature 2012, 491:374-383.
17. Pfeffer G., Horvath R., Klopstock T., Mootha V.K., Suomalainen A., Koene S., Hirano M., Zeviani M., Bindoff L.A., Yu-Wai-Man P., Hanna M., Carelli V., McFarland R., Majamaa K., Turnbull D.M., Smeitink J., Chinnery P.F. New treatments for mitochondrial disease-no time to drop our standards. Nat. Rev. Neurol. 2013, 9:474-481.
18. Goldstein A., Wolfe L.A. The elusive magic pill: finding effective therapies for mitochondrial disorders. Neurotherapeutics 2013, 10:320-328.
19. Pfeffer G., Majamaa K., Turnbull D.M., Thorburn D., Chinnery P.F. Treatment for mitochondrial disorders. Cochrane Database Syst. 2012, 4:CD004426.
20. Wenz T., Williams S.L., Bacman S.R., Moraes C.T. Emerging therapeutic approaches to mitochondrial diseases. Dev. Disabil. Res. Rev. 2010, 16:219-229.
21. Scarpelli M., Cotelli M.S., Mancuso M., Tomelleri G., Tonin P., Baronchelli C., Vielmi V., Gregorelli V., Todeschini A., Padovani A., Filosto M. Current options in the treatment of mitochondrial diseases. Recent Patents CNS Drug Discov. 2010, 5:203-209.
22. Filosto M., Mancuso M. Mitochondrial diseases: a nosological update. Acta Neurol. Scand. 2007, 115:211-221.
23. Moraes C.T., Bacman S.R., Williams S.L. Manipulating mitochondrial genomes in the clinic: playing by different rules. Trends Cell Biol. 2014, 24:209-211.
24. Mah C.S., Soustek M.S., Todd A.G., McCall A., Smith B.K., Corti M., Falk D.J., Byrne B.J. Adeno-associated virus-mediated gene therapy for metabolic myopathy. Hum. Gene Ther. 2013, 24:928-936.
25. Craven L., Elson J.L., Irving L., Tuppen H.A., Lister L.M., Greggains G.D., Byerley S., Murdoch A.P., Herbert M., Turnbull D. Mitochondrial DNA disease: new options for prevention. Hum. Mol. Genet. 2011, 20:168-174.
26. Mattson M.P., Gleichmann M., Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron 2008, 60:748-766.
27. Filosto M., Scarpelli M., Cotelli M.S., Vielmi V., Todeschini A., Gregorelli V., Tonin P., Tomelleri G., Padovani A. The role of mitochondria in neurodegenerative diseases. J. Neurol. 2011, 258:1763-1774.
28. Schapira A.H. Mitochondrial diseases. Lancet 2012, 379:1825-1834.
29. Pecina P., Houstková H., Hansíková H., Zeman J., Houstek J. Genetic defects of cytochrome c oxidase assembly. Physiol. Res. 2004, 53:S213-S223.
30. Scarpulla R.C. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 2008, 88:611-638.
31. Ekstrand M.I., Falkenberg M., Rantanen A., Park C.B., Gaspari M., Hultenby K., Rustin P., Gustafsson C.M., Larsson N.G. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum. Mol. Genet. 2004, 13:935-944.
32. Wenz T., Diaz F., Spiegelman B.M., Moraes C.T. Activation of the PPAR/PGC-1a pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008, 8:249-256.
33. Spiegelman B.M. Transcriptional control of energy homeostasis through the PGC-1 coactivators. Novartis Found. Symp. 2007, 286:3-6.
34. Casarin A., Giorgi G., Pertegato V., Siviero R., Cerqua C., Doimo M., Basso G., Sacconi S., Cassina M., Rizzuto R., Brosel S., Davidson M., DiMauro S., Schon E.A., Clementi M., Trevisson E., Salviati L. Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with SCO2 mutations. Orphanet J. Rare Dis. 2012, 19:7-21.
35. Papadopoulou L.C., Sue C.M., Davidson M.M., Tanji K., Nishino I., Sadlock J.E., Krishna S., Walker W., Selby J., Glerum D.M., Coster R.V., Lyon G., Scalais E., Lebel R., Kaplan P., Shanske S., De Vivo D.C., Bonilla E., Hirano M., DiMauro S., Schon E.A. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat. Genet. 1999, 23:333-337.
36. Salviati L., Hernandez-Rosa E., Walker W.F., Sacconi S., DiMauro S., Schon E.A., Davidson M.M. Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations. Biochem. J. 2002, 363:321-327.
37. Viscomi C., Bottani E., Civiletto G., Cerutti R., Moggio M., Fagiolari G., Schon E.A., Lamperti C., Zeviani M. In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. Cell Metab. 2011, 14:80-90.
38. Golubitzky A., Dan P., Weissman S., Link G., Wikstrom J.D., Saada A. Screening for active small molecules in mitochondrial complex I deficient patient's fibroblasts, reveals AICAR as the most beneficial compound. PLoS ONE 2011, 6:e26883.
39. Khan N.A., Auranen M., Paetau I., Pirinen E., Euro L., Forsström S., Pasila L., Velagapudi V., Carroll C.J., Auwerx J., Suomalainen A. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol. Med. 2014, 6:721-731.
40. +-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab. 2014, 10.1016/j.cmet.2014.04.001.
41. Pirinen E., Canto C., Jo Y.S., Morato L., Zhang H., Menzies K.J., Williams E.G., Mouchiroud L., Moullan N., Hagberg C., Li W., Timmers S., Imhof R., Verbeek J., Pujol A., van Loon B., Viscomi C., Zeviani M., Schrauwen P., Sauve A.A., Schoonjans K., Auwerx J. Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab. 2014, 10.1016/j.cmet.2014.04.002.
42. Lopes Costa A., Le Bachelier C., Mathieu L., Rotig A., Boneh A., De Lonlay P., Tarnopolsky M.A., Thorburn D.R., Bastin J., Djouadi F. Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum. Mol. Genet. 2014, 23:2106-2119.
43. DeStefano N., Matthews P.M., Ford B., Genge A., Karpati G., Arnold D.L. Short-term dichloracetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders. Neurology 1995, 45:1193-1198.
44. Duncan G.E., Perkins L.A., Theriaque D.W., Neiberger R.E., Stacpoole P.W. Dichloroacetate therapy attenuates the blood lactate response to submaximal exercise in patients with defects in mitochondrial energy metabolism. J. Clin. Endocrinol. Metab. 2004, 8:1733-1738.
45. Vissing J., Gansted U., Quistorff B. Exercise intolerance in mitochondrial myopathy is not related to lactic acidosis. Ann. Neurol. 2001, 49:672-676.
46. Stacpoole P.W., Kerr D.S., Barnes C., Bunch S.T., Carney P.R., Fennell E.M., Felitsyn N.M., Gilmore R.L., Greer M., Henderson G.N., Hutson A.D., Neiberger R.E., O'Brien R.G., Perkins L.A., Quisling R.G., Shroads A.L., Shuster J.J., Silverstein J.H., Theriaque D.W., Valenstein E. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 2006, 117:1519-1531.
47. Kaufmann P., Engelstad K., Wei Y., Jhung S., Sano M.C., Shungu D.C., Millar W.S., Hong X., Gooch C.L., Mao X., Pascual J.M., Hirano M., Stacpoole P.W., DiMauro S., De Vivo D.C. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006, 66:324-330.
48. Abdelmalak M., Lew A., Ramezani R., Shroads A.L., Coats B.S., Langaee T., Shankar M.N., Neiberger R.E., Subramony S.H., Stacpoole P.W. Long-term safety of dichloroacetate in congenital lactic acidosis. Mol. Genet. Metab. 2013, 109:139-143.
49. Koga Y., Akita Y., Junko N., Yatsuga S., Povalko N., Fukiyama R., Ishii M., Matsuishi T. Endothelial dysfunction in MELAS improved by l-arginine supplementation. Neurology 2006, 66:1766-1769.
50. Koga Y., Povalko N., Nishioka J., Katayama K., Kakimoto N., Matsuishi T. MELAS and l-arginine therapy: pathophysiology of stroke-like episodes. Ann. N. Y. Acad. Sci. 2010, 1201:104-110.
51. Filosto M., Mancuso M. Mitochondrial diseases. Cerebral Ischemia in Young Adults: Pathogenic and Clinical Perspectives 2009, 617-651. Nova Publishers, Hauppauge, New York, USA. A. Pezzini, A. Padovani (Eds.).
52. El-Hattab A.W., Emrick L.T., Craigen W.J., Scaglia F. Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders. Mol. Genet. Metab. 2012, 107:247-252.
53. Desquiret-Dumas V., Gueguen N., Barth M., Chevrollier A., Hancock S., Wallace D.C., Amati-Bonneau P., Henrion D., Bonneau D., Reynier P., Procaccio V. Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS. Biochim. Biophys. Acta 2012, 1822:1019-1029.
54. Yoneda M., Ikawa K., Arakawa T., Kudo H., Kimura Y., Fujibayashi H., Okazawa In vivo functional brain imaging and a therapeutic trial of l-arginine in MELAS patients. Biochim. Biophys. Acta 2012, 1820:615-618.
55. Cederbaum S.D., Blass J.P., Minkoff N., Brown W.J., Cotton M.E., Harris S.H. Sensitivity to carbohydrate in a patient with familial intermittent lactic acidosis and pyruvate dehydrogenase deficiency. Pediatr. Res. 1976, 10:713-720.
56. Wexler I.D., Hemalatha S.G., McConnell J., Buist N.R., Dahl H.H., Berry S.A., Cederbaum S.D., Patel M.S., Kerr D.S. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 1997, 49:1655-1661.
57. El-Gharbawy A.H., Boney A., Young S.P., Kishnani P.S. Follow-up of a child with pyruvate dehydrogenase deficiency on a less restrictive ketogenic diet. Mol. Genet. Metab. 2011, 102:214-215.
58. Ferriero R., Manco G., Lamantea E., Nusco E., Ferrante M.I., Sordino P., Stacpoole P.W., Lee B., Zeviani M., Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci. Transl. Med. 2013, 5:175ra31.
59. Tiranti V., Viscomi C., Hildebrandt T., Di Meo I., Mineri R., Tiveron C., Levitt M.D., Prelle A., Fagiolari G., Rimoldi M., Zeviani M. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat. Med. 2009, 15:200-205.
60. Viscomi C., Burlina A.B., Dweikat I., Savoiardo M., Lamperti C., Hildebrandt T., Tiranti V., Zeviani M. N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat. Med. 2010, 16:869-871.
61. Di Meo I., Auricchio A., Lamperti C., Burlina A., Viscomi C., Zeviani M. Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy. EMBO Mol. Med. 2012, 4:1008-1014.
62. Nishino I., Spinazzola A., Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999, 283:689-692.
63. Martí R., Spinazzola A., Tadesse S., Nishino I., Nishigaki Y., Hirano M. Definitive diagnosis of mitochondrial neurogastrointestinal encephalomyopathy by biochemical assays. Clin. Chem. 2004, 50:120-124.
64. Nishigaki Y., Martí R., Copeland W.C., Hirano M. Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J. Clin. Invest. 2003, 111:1913-1921.
65. Nishino I., Spinazzola A., Papadimitriou A., Hammans S., Steiner I., Hahn C.D., Connolly A.M., Verloes A., Guimarães J., Maillard I., Hamano H., Donati M.A., Semrad C.E., Russell J.A., Andreu A.L., Hadjigeorgiou G.M., Vu T.H., Tadesse S., Nygaard T.G., Nonaka I., Hirano I., Bonilla E., Rowland L.P., DiMauro S., Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann. Neurol. 2000, 47:792-800.
66. Filosto M., Scarpelli M., Tonin P., Testi S., Cotelli M.S., Rossi M., Salvi A., Grottolo A., Vielmi V., Todeschini A., Fabrizi G.M., Padovani A., Tomelleri G. Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy. J. Inherit. Metab. Dis. 2011, 34:1199-1203.
67. Scarpelli M., Russignan A., Zombor M., Bereczki C., Zappini F., Buono R., Bax B.E., Padovani A., Tonin P., Filosto M. Poor outcome in a mitochondrial neurogastrointestinal encephalomyopathy patient with a novel TYMP mutation: the need for early diagnosis. Case Rep. Neurol. 2012, 4:248-253.
68. Halter J., Schüpbach W.M., Casali C., Elhasid R., Fay K., Hammans S., Illa I., Kappeler L., Krähenbühl S., Lehmann T., Mandel H., Marti R., Mattle H., Orchard K., Savage D., Sue C.M., Valcarcel D., Gratwohl A., Hirano M. Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach. Bone Marrow Transplant. 2011, 46:330-337.
69. Filosto M., Scarpelli M., Tonin P., Lucchini G., Pavan F., Santus F., Parini R., Donati M.A., Cotelli M.S., Vielmi V., Todeschini A., Canonico F., Tomelleri G., Padovani A., Rovelli A. Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy. J. Neurol. 2012, 259:2699-2706.
70. Moran N.F., Bain M.D., Muquit M.M., Bax B.E. Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE. Neurology 2008, 71:686-688.
71. Bax B.E., Bain M.D., Scarpelli M., Filosto M., Tonin P., Moran N.F. Clinical and biochemical improvements in a patient with MNGIE following enzyme replacement. Neurology 2013, 81:1269-1271.
72. Torres-Torronteras J., Gómez A., Eixarch H., Palenzuela L., Pizzorno G., Hirano M., Andreu A.L., Barquinero J., Martí R. Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE. Gene Ther. 2011, 18:795-806.
73. Torres-Torronteras J., Viscomi C., Cabrera-Pérez R., Cámara Y., Di Meo I., Barquinero J., Auricchio A., Pizzorno G., Hirano M., Zeviani M., Martí R. Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE. Mol. Ther. 2014, 22:901-907.
74. Marriage B.J., Clandinin M.T., Macdonald I.M., Glerum D.M. Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders. Mol. Genet. Metab. 2004, 81:263-272.
75. Glover E.I., Martin J., Maher A., Thornhill R.E., Moran G.R., Tarnopolsky M.A. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve 2010, 42:739-748.
76. Ogasahara S., Engel A.G., Frens D., Mack D. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc. Natl. Acad. Sci. U. S. A. 1989, 86:2379-2382.
77. Quinzii C., Naini A., Salviati L., Trevisson E., Navas P., Dimauro S., Hirano M. A mutation in para-hydroxybenzoate- polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am. J. Hum. Genet. 2006, 78:345-349.
78. Montini G., Malaventura C., Salviati L. Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. N. Engl. J. Med. 2008, 358:2849-2850.
79. Geromel V., Darin N., Chrétien D., Bénit P., DeLonlay P., Rötig A., Munnich A., Rustin P. Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol. Genet. Metab. 2002, 77:21-30.
80. Carelli V., La Morgia C., Valentino M.L., Rizzo G., Carbonelli M., De Negri A.M., Sadun F., Carta A., Guerriero S., Simonelli F., Sadun A.A., Aggarwal D., Liguori R., Avoni P., Baruzzi A., Zeviani M., Montagna P., Barboni P. Idebenone treatment in Leber's hereditary optic neuropathy. Brain 2011, 134:e188.
81. Barboni P., Valentino M.L., La Morgia C., Carbonelli M., Savini G., De Negri A., Simonelli F., Sadun F., Caporali L., Maresca A., Liguori R., Baruzzi A., Zeviani M., Carelli V. Idebenone treatment in patients with OPA1-mutant dominant optic atrophy. Brain 2013, 136:e231.
82. Klopstock T., Metz G., Yu-Wai-Man P., Büchner B., Gallenmüller C., Bailie M., Nwali N., Griffiths P.G., von Livonius B., Reznicek L., Rouleau J., Coppard N., Meier T., Chinnery P.F. Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy. Brain 2013, 136:e230.
83. Enns G.M., Kinsman S.L., Perlman S.L., Spicer K.M., Abdenur J.E., Cohen B.H., Amagata A., Barnes A., Kheifets V., Shrader W.D., Thoolen M., Blankenberg F., Miller G. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol. Genet. Metab. 2012, 105:91-102.
84. Sadun A.A., Chicani C.F., Ross-Cisneros F.N., Barboni P., Thoolen M., Shrader W.D., Kubis K., Carelli V., Miller G. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch. Neurol. 2012, 69:331-338.
85. Martinelli D., Catteruccia M., Piemonte F., Pastore A., Tozzi G., Dionisi-Vici C., Pontrelli G., Corsetti T., Livadiotti S., Kheifets V., Hinman A., Shrader W.D., Thoolen M., Klein M.B., Bertini E., Miller G. EPI-743 reverses the progression of the pediatric mitochondrial disease-genetically defined Leigh syndrome. Mol. Genet. Metab. 2012, 107:383-388.
86. Tanaka M., Borgeld H.J., Zhang J., Muramatsu S., Gong J.S., Yoneda M., Maruyama W., Naoi M., Ibi T., Sahashi K., Shamoto M., Fuku N., Kurata M., Yamada Y., Nishizawa K., Akao Y., Ohishi N., Miyabayashi S., Umemoto H., Muramatsu T., Furukawa K., Kikuchi A., Nakano I., Ozawa K., Yagi K. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J. Biomed. Sci. 2002, 9:534-541.
87. Bacman S.R., Williams S.L., Garcia S., Moraes C.T. Organ-specific shifts in mtDNA heteroplasmy following systemic delivery of a mitochondria-targeted restriction endonuclease. Gene Ther. 2010, 17:713-720.
88. Bacman S.R., Williams S.L., Pinto M., Peralta S., Moraes C.T. Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs. Nat. Med. 2013, 19:1111-1113.
89. Navarro A., Boveris A. The mitochondrial energy transduction system and the aging process. Am. J. Physiol. Cell Physiol. 2007, 292:C670-C686.
90. Acin-Perez R., Hoyos B., Zhao F., Vinogradov V., Fischman D.A., Harris R.A., Leitges M., Wongsiriroj N., Blaner W.S., Manfredi G., Hammerling U. Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis. FASEB J. 2010, 24:627-636.
91. Orsucci D., Filosto M., Siciliano G., Mancuso M. Electron transfer mediators and other metabolites and cofactors in the treatment of mitochondrial dysfunction. Nutr. Rev. 2009, 67:427-438.
92. DiMauro S., Mancuso M. Mitochondrial diseases: therapeutic approaches. Biosci. Rep. 2007, 27:125-137.
93. Panetta J., Smith L.J., Boneh A. Effect of high-dose vitamins, coenzyme Q and high-fat diet in paediatric patients with mitochondrial diseases. J. Inherit. Metab. Dis. 2004, 27:487-498.
94. Lou H.C. Correction of increased plasma pyruvate and plasma lactate levels using large doses of thiamine in patients with Kearns-Sayre syndrome. Arch. Neurol. 1981, 38:469.
95. Mayr J.A., Freisinger P., Schlachter K., Rolinski B., Zimmermann F.A., Scheffner T., Haack T.B., Koch J., Ahting U., Prokisch H., Sperl W. Thiamine deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am. J. Hum. Genet. 2011, 89:806-812.
96. Barnerias C., Saudubray J.M., Touati G., De Lonlay P., Dulac O., Ponsot G., Marsac C., Brivet M., Desguerre I. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev. Med. Child Neurol. 2010, 52:e1-e9.
97. Gerards M., Kamps R., van Oevelen J., Boesten I., Jongen E., de Koning B., Scholte H.R., de Angst I., Schoonderwoerd K., Sefiani A., Ratbi I., Coppieters W., Karim L., de Coo R., van den Bosch B., Smeets H. Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain 2013, 136:882-890.
98. Saijo T., Tanaka K. Isoalloxazine ring of FAD is required for the formation of the core in the Hsp60-assisted folding of medium chain acyl-CoA dehydrogenase subunit into the assembly competent conformation in mitochondria. J. Biol. Chem. 1995, 270:1899-1907.
99. Olsen R.K., Olpin S.E., Andresen B.S., Miedzybrodzka Z.H., Pourfarzam M., Merinero B., Frerman F.E., Beresford M.W., Dean J.C., Cornelius N., Andersen O., Oldfors A., Holme E., Gregersen N., Turnbull D.M., Morris A.A. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 2007, 130:2045-2054.
100. Grad L.I., Lemire B.D. Riboflavin enhances the assembly of mitochondrial cytochrome c oxidase in C. elegans NADH-ubiquinone oxidoreductase mutants. Biochim. Biophys. Acta 2006, 1757:115-122.
101. Gerards M., van den Bosch B.J., Danhauser K., Serre V., van Weeghel M., Wanders R.J., Nicolaes G.A., Sluiter W., Schoonderwoerd K., Scholte H.R., Prokisch H., Rötig A., de Coo I.F., Smeets H.J. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain 2011, 134:210-219.
102. Garone C., Donati M.A., Sacchini M., Garcia-Diaz B., Bruno C., Calvo S., Mootha V.K., DiMauro S. Mitochondrial encephalomyopathy due to a novel mutation in ACAD9. JAMA Neurol. 2013, 70:1177-1179.
103. Ghezzi D., Sevrioukova I., Invernizzi F., Lamperti C., Mora M., D'Adamo P., Novara F., Zuffardi O., Uziel G., Zeviani M. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am. J. Hum. Genet. 2010, 86:639-649.
104. Garrido-Maraver J., Cordero M.D., Moñino I.D., Pereira-Arenas S., Lechuga-Vieco A.V., Cotán D., De la Mata M., Oropesa-Ávila M., De Miguel M., Bautista Lorite J., Rivas Infante E., Alvarez-Dolado M., Navas P., Jackson S., Francisci S., Sánchez-Alcázar J.A. Screening of effective pharmacological treatments for MELAS syndrome using yeasts, fibroblasts and cybrid models of the disease. Br. J. Pharmacol. 2012, 167:1311-1328.
105. Remes A.M., Liimatta E.V., Winqvist S., Tolonen U., Ranua J.A., Reinikainen K., Hassinen I.E., Majamaa K. Ubiquinone and nicotinamide treatment of patients with the 3243A>G mtDNA mutation. Neurology 2002, 59:1275-1277.
106. Garcia-Cazorla A., Quadros E.V., Nascimento A., Garcia-Silva M.T., Briones P., Montoya J., Ormazábal A., Artuch R., Sequeira J.M., Blau N., Arenas J., Pineda M., Ramaekers V.T. Mitochondrial diseases associated with cerebral folate deficiency. Neurology 2008, 70:1360-1362.
107. Pineda M., Ormazabal A., López-Gallardo E., Nascimento A., Solano A., Herrero M.D., Vilaseca M.A., Briones P., Ibáñez L., Montoya J., Artuch R. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann. Neurol. 2006, 59:394-398.
108. Gordon N. Cerebral folate deficiency. Dev. Med. Child Neurol. 2009, 51:180-182.
109. Rahman S., Hanna M.G. Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases. J. Neurol. Neurosurg. Psych. 2009, 80:943-953.
110. Singh R., Sripada L., Singh R. Side effects of antibiotics during bacterial infection: mitochondria, the main target in host cell. Mitochondrion 2014, 16:50-54.
111. Orsucci D., Mancuso M., Filosto M., Siciliano G. Tetracyclines and neuromuscular disorders. Curr. Neuropharmacol. 2012, 10:134-138.
112. Mancuso M., Orsucci D., Calsolaro V., LoGerfo A., Allegrini L., Petrozzi L., Simoncini C., Rocchi A., Trivella F., Murri L., Siciliano G. Tetracycline treatment in patients with progressive external ophthalmoplegia. Acta Neurol. Scand. 2011, 124:417-423.
113. Lands L.C., Grey V.L., Smountas A.A. Effect of supplementation with a cysteine donor on muscular performance. J. Appl. Physiol. 1999, 87:1381-1385.
114. Hargreaves I.P., Sheena Y., Land J.M., Heales S.J. Glutathione deficiency in patients with mitochondrial disease: implications for pathogenesis and treatment. J. Inherit. Metab. Dis. 2005, 28:81-88.
115. Mancuso M., Orsucci D., Logerfo A., Rocchi A., Petrozzi L., Nesti C., Galetta F., Santoro G., Murri L., Siciliano G. Oxidative stress biomarkers in mitochondrial myopathies, basally and after cysteine donor supplementation. J. Neurol. 2010, 257:774-781.
116. Couplan E., Aiyar R.S., Kucharczyk R., Kabala A., Ezkurdia N., Gagneur J., St Onge R.P., Salin B., Soubigou F., Le Cann M., Steinmetz L.M., di Rago J.P., Blondel M. A yeast-based assay identifies drugs active against human mitochondrial disorders. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:11989-11994.
117. Brini M., Pinton P., King M.P., Davidson M., Schon E.A., Rizzuto R. A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. Nat. Med. 1999, 5:951-954.
118. 2+ handling in human complex I deficiency. J. Biol. Chem. 2004, 279:40328-40336.
119. Alavian K.N., Dworetzky S.I., Bonanni L., Zhang P., Sacchetti S., Mariggio M.A., Onofrj M., Thomas A., Li H., Mangold J.E., Signore A.P., Demarco U., Demady D.R., Nabili P., Lazrove E., Smith P.J., Gribkoff V.K., Jonas E.A. Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. Brain Res. 2012, 1446:1-11.
120. Alberio S., Mineri R., Tiranti V., Zeviani M. Depletion of mtDNA: syndromes and genes. Mitochondrion 2007, 7:6-12.
121. Saada A. Mitochondrial deoxyribonucleotide pools in deoxyguanosine kinase deficiency. Mol. Genet. Metab. 2008, 95:169-173.
122. Taanman J.W., Muddle J.R., Muntau A.C. Mitochondrial DNA depletion can be prevented by dGMP and dAMP supplementation in a resting culture of deoxyguanosine kinase-deficient fibroblasts. Hum. Mol. Genet. 2003, 12:1839-1845.
123. Bulst S., Abicht A., Holinski-Feder E., Müller-Ziermann S., Koehler U., Thirion C., Walter M.C., Stewart J.D., Chinnery P.F., Lochmüller H., Horvath R. In vitro supplementation with dAMP/dGMP leads to partial restoration of mtDNA levels in mitochondrial depletion syndromes. Hum. Mol. Genet. 2009, 18:1590-1599.
124. Bulst S., Holinski-Feder E., Payne B., Abicht A., Krause S., Lochmüller H., Chinnery P.F., Walter M.C., Horvath R. In vitro supplementation with deoxynucleoside monophosphates rescues mitochondrial DNA depletion. Mol. Genet. Metab. 2012, 107:95-103.
125. González-Vioque E., Torres-Torronteras J., Andreu A.L., Martí R. Limited dCTP availability accounts for mitochondrial DNA depletion in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). PLoS Genet. 2011, 7:e1002035.
126. Cámara Y., González-Vioque E., Scarpelli M., Torres-Torronteras J., Martí R. Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA. Drug Discov. Today 2013, 18:950-957.
127. Cámara Y., González-Vioque E., Scarpelli M., Torres-Torronteras J., Caballero A., Hirano M., Martí R. Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome. Hum. Mol. Genet. 2014, 23:2459-2467.