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Current and Emerging Therapies for Mitochondriopathies

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Pediatric Pharmacotherapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 261))

Abstract

Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders. The underlying dysfunction of the mitochondrial electron transport chain and oxidative phosphorylation is caused by variants of genes encoding mitochondrial proteins. Despite substantial advances in the understanding of the mechanism of these diseases, there are still no satisfactory therapies available. Therapeutic strategies include the use of antioxidants, inducers of mitochondrial biogenesis, enhancers of electron transfer chain function, energy buffers, amino acids restoring NO production, nucleotide bypass therapy, liver transplantation, and gene therapy. Although there are some promising projects underway, to date satisfactory therapies are missing.

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References

  • Abdelmalak M, Lew A, Ramezani R, Shroads AL, Coats BS, Langaee T, Shankar MN, Neiberger RE, Subramony SH, Stacpoole PW (2013) Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab 109:139–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

    Article  CAS  PubMed  Google Scholar 

  • Barshop BA, Naviaux RK, McGowan KA, Levine F, Nyhan WL, Loupis-Geller A, Haas RH (2004) Chronic treatment of mitochondrial disease patients with dichloroacetate. Mol Genet Metab 83:138–149

    Article  CAS  PubMed  Google Scholar 

  • Bernsen PL, Gabreels FJ, Ruitenbeek W, Hamburger HL (1993) Treatment of complex I deficiency with riboflavin. J Neurol Sci 118:181–187

    Article  CAS  PubMed  Google Scholar 

  • Bugiani M, Lamantea E, Invernizzi F, Moroni I, Bizzi A, Zeviani M, Uziel G (2006) Effects of riboflavin in children with complex II deficiency. Brain Dev 28:576–581

    Article  PubMed  Google Scholar 

  • Chinnery P (2014) Mitochondrial disorders overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ (eds) GeneReviews®. University of Washington, Seattle

    Google Scholar 

  • El-Hattab AW, Scaglia F (2013) Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 10:186–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Hattab AW, Hsu JW, Emrick LT, Wong LJ, Craigen WJ, Jahoor F, Scaglia F (2012) Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Mol Genet Metab 105:607–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Hattab AW, Emrick LT, Hsu JW, Chanprasert S, Almannai M, Craigen WJ, Jahoor F, Scaglia F (2016) Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation. Mol Genet Metab 117:407–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Hattab AW, Zarante AM, Almannai M, Scaglia F (2017) Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab 122:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garone C, Donati MA, Sacchini M, Garcia-Diaz B, Bruno C, Calvo S, Mootha VK, Dimauro S (2013) Mitochondrial encephalomyopathy due to a novel mutation in ACAD9. JAMA Neurol 70:1177–1179

    Article  PubMed  PubMed Central  Google Scholar 

  • Glover EI, Martin J, Maher A, Thornhill RE, Moran GR, Tarnopolsky MA (2010) A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve 42:739–748

    Article  CAS  PubMed  Google Scholar 

  • Golubitzky A, Dan P, Weissman S, Link G, Wikstrom JD, Saada A (2011) Screening for active small molecules in mitochondrial complex I deficient patient’s fibroblasts, reveals AICAR as the most beneficial compound. PLoS One 6:e26883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guy J, Feuer WJ, Davis JL, Porciatti V, Gonzalez PJ, Koilkonda RD, Yuan H, Hauswirth WW, Lam BL (2017) Gene therapy for leber hereditary optic neuropathy: low- and medium-dose visual results. Ophthalmology 124:1621–1634

    Article  PubMed  Google Scholar 

  • Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J et al (2010) Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet 42:1131–1134

    Article  CAS  PubMed  Google Scholar 

  • Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH (2018) Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology 90:e1212–e1221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato M, Li J, Chuang JL, Chuang DT (2007) Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure 15:992–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X et al (2006) Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66:324–330

    Article  CAS  PubMed  Google Scholar 

  • Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A et al (2011) A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain 134:2677–2686

    Article  PubMed  PubMed Central  Google Scholar 

  • Klopstock T, Metz G, Yu-Wai-Man P, Buchner B, Gallenmuller C, Bailie M, Nwali N, Griffiths PG, von Livonius B, Reznicek L et al (2013) Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain 136:e230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Tanabe Y, Fujimoto S, Matsuishi T (2005) L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 64:710–712

    Article  CAS  PubMed  Google Scholar 

  • Koga Y, Akita Y, Junko N, Yatsuga S, Povalko N, Fukiyama R, Ishii M, Matsuishi T (2006) Endothelial dysfunction in MELAS improved by l-arginine supplementation. Neurology 66:1766–1769

    Article  CAS  PubMed  Google Scholar 

  • Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Katayama K, Matsuishi T (2007) MELAS and L-arginine therapy. Mitochondrion 7:133–139

    Article  CAS  PubMed  Google Scholar 

  • Komen JC, Thorburn DR (2014) Turn up the power – pharmacological activation of mitochondrial biogenesis in mouse models. Br J Pharmacol 171:1818–1836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Libri V, Brown AP, Gambarota G, Haddad J, Shields GS, Dawes H, Pinato DJ, Hoffman E, Elliot PJ, Vlasuk GP et al (2012) A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers. PLoS One 7:e51395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mermigkis C, Bouloukaki I, Mastorodemos V, Plaitakis A, Alogdianakis V, Siafakas N, Schiza S (2013) Medical treatment with thiamine, coenzyme Q, vitamins E and C, and carnitine improved obstructive sleep apnea in an adult case of Leigh disease. Sleep Breath 17:1129–1135

    Article  PubMed  Google Scholar 

  • Moroni I, Bugiani M, Bizzi A, Castelli G, Lamantea E, Uziel G (2002) Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics 33:79–85

    Article  CAS  PubMed  Google Scholar 

  • Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, Liby KT, Risingsong R, Sporn M, Beal MF et al (2011) Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med 51:88–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noe N, Dillon L, Lellek V, Diaz F, Hida A, Moraes CT, Wenz T (2013) RETRACTED: bezafibrate improves mitochondrial function in the CNS of a mouse model of mitochondrial encephalopathy. Mitochondrion 13:417–426

    Article  CAS  PubMed  Google Scholar 

  • Nogueira L, Ramirez-Sanchez I, Perkins GA, Murphy A, Taub PR, Ceballos G, Villarreal FJ, Hogan MC, Malek MH (2011) (−)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle. J Physiol 589:4615–4631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N et al (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain J Neurol 130:2045–2054

    Article  Google Scholar 

  • Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM (2009) A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol 11:414–430

    Article  PubMed  PubMed Central  Google Scholar 

  • Perez-Duenas B, Serrano M, Rebollo M, Muchart J, Gargallo E, Dupuits C, Artuch R (2013) Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency. Pediatrics 131:e1670–e1675

    Article  PubMed  Google Scholar 

  • Rai PK, Russell OM, Lightowlers RN, Turnbull DM (2015) Potential compounds for the treatment of mitochondrial disease. Br Med Bull 116:5–18

    CAS  PubMed  Google Scholar 

  • Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA (2007) Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 35:235–242

    Article  CAS  PubMed  Google Scholar 

  • Rudolph G, Dimitriadis K, Buchner B, Heck S, Al-Tamami J, Seidensticker F, Rummey C, Leinonen M, Meier T, Klopstock T (2013) Effects of idebenone on color vision in patients with leber hereditary optic neuropathy. J Neuroophthalmol 33:30–36

    Article  PubMed  PubMed Central  Google Scholar 

  • Sato Y, Nakagawa M, Higuchi I, Osame M, Naito E, Oizumi K (2000) Mitochondrial myopathy and familial thiamine deficiency. Muscle Nerve 23:1069–1075

    Article  CAS  PubMed  Google Scholar 

  • Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN et al (2006) Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117:1519–1531

    Article  PubMed  Google Scholar 

  • Szeto HH (2014) First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol 171:2029–2050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarnopolsky MA, Parise G (1999) Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve 22:1228–1233

    Article  CAS  PubMed  Google Scholar 

  • Tarnopolsky MA, Roy BD, MacDonald JR (1997) A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 20:1502–1509

    Article  CAS  PubMed  Google Scholar 

  • Tengan CH, Kiyomoto BH, Godinho RO, Gamba J, Neves AC, Schmidt B, Oliveira AS, Gabbai AA (2007) The role of nitric oxide in muscle fibers with oxidative phosphorylation defects. Biochem Biophys Res Commun 359:771–777

    Article  CAS  PubMed  Google Scholar 

  • Wexler ID, Hemalatha SG, McConnell J, Buist NR, Dahl HH, Berry SA, Cederbaum SD, Patel MS, Kerr DS (1997) Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 49:1655–1661

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute for Inborn Errors of Metabolism and Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria

    Florian B. Lagler

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  1. Florian B. Lagler
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Correspondence to Florian B. Lagler .

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Editors and Affiliations

  1. Hospital for Children and Adolescents Center of Paediatric Research Department of Women and Child Health, University of Leipzig, Leipzig, Germany

    Wieland Kiess

  2. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Department of Clinical Pharmacology, University Hospital Tüebingen, Tüebingen, Germany, Robert Bosch Gesellschaft fuer medizinische Forschung mbH, Stuttgart, Germany

    Matthias Schwab

  3. Children’s Hospital, University of Basel Children’s Hospital, Basel, Switzerland

    Johannes van den Anker

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Lagler, F.B. (2019). Current and Emerging Therapies for Mitochondriopathies. In: Kiess, W., Schwab, M., van den Anker, J. (eds) Pediatric Pharmacotherapy . Handbook of Experimental Pharmacology, vol 261. Springer, Cham. https://doi.org/10.1007/164_2019_264

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