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Pathogenesis and Treatment of Mitochondrial Disorders

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Inherited Neuromuscular Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 652))

Abstract

In the past 50 years, our understanding of the biochemical and molecular causes of mitochondrial diseases, defined restrictively as disorders due to defects of the mitochondrial respiratory chain (RC), has made great strides. Mitochondrial diseases can be due to mutations in mitochondrial DNA (mtDNA) or in nuclear DNA (nDNA) and each group can be subdivided into more specific classes. Thus, mtDNA-related disorders can result from mutations in genes affecting protein synthesis in toto or mutations in protein-coding genes. Mendelian mitochondrial disorders can be attributed to mutations in genes that (i) encode subunits of the RC (“direct hits”); (ii) encode assembly proteins or RC complexes (“indirect hits”); (iii) encode factors needed for mtDNA maintenance, replication, or translation (intergenomic signaling); (iv) encode components of the mitochondrial protein import machinery; (v) control the synthesis and composition of mitochondrial membrane phospholipids; and (vi) encode proteins involved in mitochondrial dynamics.

In contrast to this wealth of knowledge about etiology, our understanding of pathogenic mechanism is very limited. We discuss pathogenic factors that can influence clinical expression, especially ATP shortage and reactive oxygen radicals (ROS) excess.

Therapeutic options are limited and fall into three modalities: (i) symptomatic interventions, which are palliative but crucial for day-to-day management; (ii) radical approaches aimed at correcting the biochemical or molecular error, which are interesting but still largely experimental; and (iii) pharmacological means of interfering with the pathogenic cascade of events (e.g. boosting ATP production or scavenging ROS), which are inconsistently and incompletely effective, but can be safe and helpful.

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Abbreviations

AD::

Alzheimer disease

Allo-SCT::

allogeneic stem cell transplantation

ALS::

amyotrophic lateral sclerosis

ANT1::

adenine nucleotide transporter 1

AOA1::

Ataxia oculomotor apraxia type 1

APTX::

aprataxin

AIF::

apoptosis inducing factor

AZT::

azidothymidine

BCS1L::

cytochrome b-c complex assembly protein (complex III)

Bi-PAP::

bilevel positive air pressure

CACT::

carnitine-acylcarnitine translocase

CMT::

Charcot-Marie-Tooth

CoQ::

coenzyme Q (ubiquinone)

COX::

cytochrome c oxidase

CPAP::

continuous positive air pressure

CPT::

carnitine palmitoyltransferase

CSF::

cerebrospinal fluid

DARS2::

gene encoding mitochondrial aspartyl-tRNA synthetase

DCA::

dichloroacetate

DIC::

dicarboxylate carrier

DDP1::

deafness dystonia protein 1

DGUOK::

deoxyguanosine kinase

DOA::

dominant optic atrophy

EFG1::

gene encoding elongation factor 1

ETF::

electron transfer flavoprotein

EFTDH::

electron transfer flavoprotein dehydrogenase

EFTu::

elongation factor Tu

ENT::

ear-nose-throat

FA::

Friedreich ataxia

FBSN::

familial bilateral striatal necrosis

GA::

glutaric aciduria

GDAP1::

ganglioside-induced differentiation protein 1

HSP::

hereditary spastic paraplegia

KSS::

Kearns-Sayre syndrome

LBSL::

leukoencephalopathy. brain stem, spinal cord involvement and lactate elevation

LHON::

Leber hereditary optic neuropathy

LPRRC::

leucine-rich pentatricopeptide repeat-containing protein

LS::

Leigh syndrome

MELAS::

mitochondrial encephalopathy, lactic acidosis, and strokelike episodes

MERRF::

myoclonus epilepsy and ragged-red fibers

MFN::

mitofusin

MILS::

maternally inherited Leigh syndrome

MND::

motor neuron disease

MNGIE::

mitochondrial neurogastrointestinal encephalomyopathy

MPV17::

MPV17 mitochondrial inner membrane protein (SYM1)

MRI::

magnetic resonance imaging

MRS::

magnetic resonance spectroscopy

mtDNA::

mitochondrial DNA

NARP::

neuropathy, ataxia, retinitis pigmentosa

ND::

NADH-coenzyme Q oxidoreductase

nDNA::

nuclear DNA

NNH::

Navajo neurohepatopathy

NO::

nitric oxide

OPA1::

dynamin-related GTPase mutated in autosomal dominant optic atrophy

PD::

Parkinson disease

PDHC::

pyruvate dehydrogenase complex

PDSS2::

decaprenyl diphosphate synthase subunit 2

PEO::

progressive external ophthalmoplegia

PNAS::

peptide nucleic acids

POLG::

polymerase γ

PUS1::

pseudouridine synthase 1

RC::

respiratory chain

RRF::

ragged-red fibers

ROS::

reactive oxygen species

SCO::

synthesis of cytochrome c oxidase

SCS-A::

succinyl-CoA synthetase

SDH::

succinate dehydrogenase

SUCLA2::

gene encoding the β subunit of succinyl-CoA synthetase

SUCLG1::

gene encoding the α subunit of succinyl-CoA synthetase

SURF1::

surfeit gene 1

TAZ::

tafazzin

TCA::

tricarboxylic acid cycle (Krebs cycle)

TIM::

translocase of the inner membrane

TK2::

thymidine kinase 2

TP::

thymidine phosphorylase

TYMP::

the gene encoding thymidine phosphoylase

References

  1. Luft R, Ikkos D, Palmieri G, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  2. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988;242:1427–1430.

    Article  CAS  PubMed  Google Scholar 

  3. Holt IJ, Harding AE, Morgan Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717–719.

    Article  CAS  PubMed  Google Scholar 

  4. Luft R. The development of mitochondrial medicine. Proc. Natl. Acad. Sci. USA 1994;91:8731–8738.

    Article  CAS  PubMed  Google Scholar 

  5. Gvozdjáková A, ed. Mitochondrial Medicine: Springer, 2008.

    Google Scholar 

  6. DiMauro S, Hirano M, Schon EA, eds. Mitochondrial Medicine. Abingdon, UK: Informa Healthcare, 2006.

    Google Scholar 

  7. Shy GM, Gonatas NK. Two childhood myopathies with abnormal mitochondria: I. Megaconial myopathy; II. Pleoconial myopathy. Brain 1966;89:133–158.

    CAS  Google Scholar 

  8. Shy GM, Gonatas NK. Human myopathy with giant abnormal mitochondria. Science 1964;145:493–496.

    Article  CAS  PubMed  Google Scholar 

  9. Engel WK, Cunningham CG. Rapid examination of muscle tissue: An improved trichrome stain method for fresh-frozen biopsy sections. Neurology 1963;13:919–923.

    CAS  PubMed  Google Scholar 

  10. Shapira Y, Harel S, Russell A. Mitochondrial encephalomyopathies: a group of neuromuscular disorders with defects in oxidative metabolism. Isr. J. Med. Sci. 1977;13:161–164.

    CAS  PubMed  Google Scholar 

  11. Mitomap. MITOMAP: A human mitochondrial genome database. http://www.mitomap.org. 2003.

  12. Sproule D, KaufmannP. Mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS): A review of basic concepts, the clinical phenotype, and therapeutic management. Ann. NY Acad. Sci. 2008;1142:133–158.

    Google Scholar 

  13. Shanske S, Coku J, Lu J, et al. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome. Arch. Neurol. 2008;65:368–372.

    Article  PubMed  Google Scholar 

  14. Manwaring N, Jones MM, Wang JJ, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion 2007;7:230–233.

    Article  CAS  PubMed  Google Scholar 

  15. Elliott HR, Samuels DC, Eden JA, et al. Pathogenic mitochondrial DNA mutations are common in the general population. Am. J. Hum. Genet. 2008;83:254–260.

    Google Scholar 

  16. Santorelli FM, Shanske S, Macaya A, et al. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh syndrome. Ann Neurol. 1993;34:827–834.

    Article  CAS  PubMed  Google Scholar 

  17. Holt IJ, Harding AE, Petty RK, Morgan Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990;46:428–433.

    CAS  PubMed  Google Scholar 

  18. Carelli V, Barboni P, Sadun AA. Mitochondrial ophthalmology. In: DiMauro S, Hirano M, Schon EA, eds. Mitochondrial Medicine. London: Informa Healthcare, 2006:105–142.

    Google Scholar 

  19. Andreu AL, Hanna MG, Reichmann H, et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. New Engl. J. Med. 1999;341:1037–1044.

    Article  CAS  PubMed  Google Scholar 

  20. Massa V, Fernandez-Vizarra E, Alshahwan S, et al. Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am. J. Hum. Genet. 2008;doi:10.1016/j.ajhg.2008.05.002.

    Google Scholar 

  21. Di Giovanni S, Mirabella M, Spinazzola A, et al. Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 2001;57:515–518.

    PubMed  Google Scholar 

  22. Sobreira C, Hirano M, Shanske S, et al. Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. Neurology 1997;48:1238–1243.

    CAS  PubMed  Google Scholar 

  23. Ogasahara S, Engel AG, Frens D, Mack D. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Nat Acad Sci USA 1989;86:2379–2382.

    Article  CAS  PubMed  Google Scholar 

  24. Gironi M, Lamperti C, Nemni R, et al. Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 2004;62:818–820.

    CAS  PubMed  Google Scholar 

  25. Lamperti C, Naini A, Hirano M, et al. Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 2003;60:1206–1208.

    CAS  PubMed  Google Scholar 

  26. Musumeci O, Naini A, Slonim AE, et al. Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 2001;56:849–855.

    CAS  PubMed  Google Scholar 

  27. Lalani S, Vladutiu GD, Plunkett K, et al. Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch Neurol 2005;62:317–320.

    Article  PubMed  Google Scholar 

  28. Salviati L, Sacconi S, Murer L, et al. Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 2005;65:606–608.

    Article  CAS  PubMed  Google Scholar 

  29. Rotig A, Appelkvist E-L, Geromel V, et al. Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet 2000;356:391–395.

    Article  CAS  PubMed  Google Scholar 

  30. Van Maldergem L, Trijbels F, DiMauro S, et al. Coenzyme Q-responsive Leigh’s encephalopathy in two sisters. Ann Neurol 2002;52:750–754.

    Article  PubMed  CAS  Google Scholar 

  31. Diomedi-Camassei F, Di Giandomenico S, Santorelli F, et al. COQ2 nephropathy: A newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 2007;18:2773–2780.

    Article  CAS  PubMed  Google Scholar 

  32. Quinzii C, Kattah AG, Naini A, et al. Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology 2005;64:539–541.

    CAS  PubMed  Google Scholar 

  33. Gempel K, Topaloglu H, Talim B, et al. The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 2007;130:2037–2044.

    Article  PubMed  Google Scholar 

  34. Lopez LC, Quinzii C, Schuelke M, et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaproneyl diphosphate synthase subunit 2 (PDSS2) mutations. Am. J. Hum. Genet. 2006;79:1125–1129.

    Google Scholar 

  35. Mollet J, Giurgea I, Schlemmer D, et al. Prenyldiphosphate synthase (PDSS1) and OH-benzoate prenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. J. Clin. Invest. 2007;117:765–772.

    Article  CAS  PubMed  Google Scholar 

  36. Quinzii C, Naini A, Salviati L, et al. A mutation in para-Hydoxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am. J. Hum. Genet. 2006;78:345–349.

    Article  CAS  PubMed  Google Scholar 

  37. Lagier-Tourenne C, Tazir M, Lopez LC, et al. ADSK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am. J. Hum. Genet. 2008;82:661–672.

    Article  CAS  PubMed  Google Scholar 

  38. Mollet J, Delahodde A, Serre V, et al. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am. J. Hum. Genet. 2008;82:623–630.

    Article  CAS  PubMed  Google Scholar 

  39. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu. Rev. Neurosci. 2008;31:91–123.

    Article  CAS  PubMed  Google Scholar 

  40. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999;283:689–692.

    Article  CAS  PubMed  Google Scholar 

  41. Hirano M, Silvestri G, Blake D, et al. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Clinical, biochemical and genetic features of an autosomal recessive mitochondrial disorder. Neurology 1994;44:721–727.

    CAS  PubMed  Google Scholar 

  42. Kaukonen J, Juselius JK, Tiranti V, et al. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 2000;289:782–785.

    Article  CAS  PubMed  Google Scholar 

  43. Spelbrink JN, Li FY, Tiranti V, et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nature Genet. 2001;28:200–201.

    Article  Google Scholar 

  44. Van Goethem G, Dermaut B, Lofgren A, et al. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genet. 2001;28:211–212.

    Article  PubMed  CAS  Google Scholar 

  45. Graziewicz MA, Longley MJ, Copeland WC. DNA polymerade gamma in mitochondrial DNA replication and repair. Chem. Rev. 2006;106:385–405.

    Article  CAS  Google Scholar 

  46. Longley MJ, Clark S, Man CYW, et al. Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Am. J. Hum. Genet. 2006;78:1026–1034.

    Article  CAS  PubMed  Google Scholar 

  47. Zanna C, Ghelli A, Porcelli AM, et al. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 2008;131:352–367.

    Article  PubMed  Google Scholar 

  48. Ferraris S, Clark S, Garelli E, et al. Perogressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1. Arch. Neurol. 2008;65:125–131.

    Article  PubMed  Google Scholar 

  49. Hudson G, Amati-Bonneau P, Blakeley E, et al. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain 2007;131:329–337.

    Article  PubMed  Google Scholar 

  50. Amati-Bonneau P, Guichet A, Olichon A, et al. OPA1 R445H mutation in optic atrophy associated with sensorinaural deafness. Ann. Neurol. 2005;58:958–963.

    Article  CAS  PubMed  Google Scholar 

  51. Spinazzola A, Zeviani M. Disorders of nuclear-mitochondrial intergenomic signaling. Gene 2005;354:162–168.

    Article  CAS  PubMed  Google Scholar 

  52. Oskoui M, Davidzon G, Pascual J, et al. Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Arch. Neurol. 2006;63:1122–1126.

    Article  PubMed  Google Scholar 

  53. Ostergaard E, Christensen E, Kristensen E, et al. Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am. J. Hum. Genet. 2007;81:383–387.

    Article  CAS  PubMed  Google Scholar 

  54. Elpeleg O, Miller C, Hershkovitz E, et al. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am. J. Hum. Genet. 2005;76:1081–1086.

    Article  CAS  PubMed  Google Scholar 

  55. Freisinger P, Futterer N, Lankes E, et al. Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations. Arch. Neurol. 2006;63:1129–1134.

    Article  PubMed  Google Scholar 

  56. Mandel H, Szargel R, Labay V, et al. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nature Genet. 2001;29:337–341.

    Article  CAS  PubMed  Google Scholar 

  57. Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol. 2004;55:706–712.

    Article  CAS  PubMed  Google Scholar 

  58. Spinazzola A, Viscomi C, Fernandez-Vizarra E, et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. . Nature Genet. 2006;38:570–575.

    Article  CAS  PubMed  Google Scholar 

  59. Karadimas CL, Vu TH, Holve SA, et al. Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Am. J. Hum. Genet. 2006;79:544–548.

    Article  CAS  PubMed  Google Scholar 

  60. Jacobs HT, Turnbull DM. Nuclear genes and mitochondrial translation: a new class of genetic disease. Trends Genet. 2005;21:312–314.

    Article  CAS  PubMed  Google Scholar 

  61. Antonicka H, Sasarman F, Kennaway NG, Shoubridge EA. The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. Hum. Mol. Genet. 2006;15:1835–1846.

    Article  CAS  PubMed  Google Scholar 

  62. Miller C, Saada A, Shaul N, et al. Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann. Neurol. 2004;56:734–738.

    Article  CAS  PubMed  Google Scholar 

  63. Smeitink JAM, Elpeleg O, Antonicka H, et al. Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am. J. Hum. Genet. 2006;79:869–877.

    Article  CAS  PubMed  Google Scholar 

  64. Fernandez-Vizarra E, Berardinelli A, Valente L, et al. Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anemia (MLASA). J. Med. Genet. 2007;44:173–180.

    Google Scholar 

  65. Bykhovskaya Y, Casas KA, Mengesha E, et al. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am. J. Hum. Genet. 2004;74:1303–1308.

    Article  CAS  PubMed  Google Scholar 

  66. Scheper GC, van der Klok T, van Andel RJ. et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nature Genet. 2007;39:534–538.

    Article  CAS  PubMed  Google Scholar 

  67. Chan DC. Mitochondrial dynamics in disease. New Engl. J. Med. 2007;356:1707–1709.

    Article  CAS  PubMed  Google Scholar 

  68. Fichera M, Lo Giudice M, Falco M, et al. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology 2004;63:1108–1110.

    CAS  PubMed  Google Scholar 

  69. Delettre C, Lenaers G, Griffoin J-M, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nature Genet. 2000;26:207–210.

    Article  CAS  PubMed  Google Scholar 

  70. Alexander C, Votruba M, Pesch UEA, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genet. 2000;26:211–215.

    Article  CAS  PubMed  Google Scholar 

  71. Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005;65:197–204.

    Article  CAS  PubMed  Google Scholar 

  72. Zuchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature Genet. 2004;36:449–451.

    Article  PubMed  CAS  Google Scholar 

  73. Pedrola L, Espert A, Wu X, et al. GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Hum. Mol. Genet. 2005;14:1087–1094.

    Article  CAS  PubMed  Google Scholar 

  74. Niemann A, Ruegg M, La Padula V, et al. Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J. Cell Biol. 2005;170:1067–1078.

    Article  CAS  PubMed  Google Scholar 

  75. Barth PG, Wanders RJA, Vreken P, et al. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 30260). J. Inher. Metab. Dis. 1999;22:555–567.

    Article  CAS  PubMed  Google Scholar 

  76. Bione S, D’Adamo P, Maestrini E, et al. A novel X-linked gene, G4.5, is responsible for Barth syndrome. Nature Genet. 1996;12:385–389.

    Article  CAS  PubMed  Google Scholar 

  77. Schlame M, Ren M. Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett. 2006;580:5450–5455.

    Article  CAS  PubMed  Google Scholar 

  78. Roesch K, Curran SP, Tranebjaerg L, Koehler CM. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum. Mol. Genet. 2002;11:477–486.

    Article  CAS  PubMed  Google Scholar 

  79. Parone PA, Da Cruz S, Tondera D, et al. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 2008;3:e 3257.

    Article  CAS  Google Scholar 

  80. King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 1989;246:500–503.

    Article  CAS  PubMed  Google Scholar 

  81. Chomyn A, Martinuzzi A, Yoneda M, et al. MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. Natl. Acad. Sci. USA 1992;89:4221–4225.

    Article  CAS  PubMed  Google Scholar 

  82. Chinnery PF, Taylor DJ, Brown DT, et al. Very low levels of the mtDNA A3243G mutation associated with mitochondrial dysfunction in vivo. Ann. Neurol. 2000;47:381–384.

    Article  CAS  PubMed  Google Scholar 

  83. Kaufmann P, Shungu D, Sano MC, et al. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology 2004;62:1297–1302.

    CAS  PubMed  Google Scholar 

  84. Tatuch Y, Christodoulou J, Feigenbaum A, et al. Heteroplasmic mtDNA mutation (T>G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am. J. Hum. Genet. 1992;50:852–858.

    CAS  PubMed  Google Scholar 

  85. Carelli V, Baracca A, Barogi S, et al. Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation. Arch. Neurol. 2002;59:264–270.

    Article  PubMed  Google Scholar 

  86. Sgarbi G, Baracca A, Lenaz G, et al. Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. Biochem. J. 2006;395:493–500.

    Article  CAS  PubMed  Google Scholar 

  87. Tanji K, Schon EA, DiMauro S, Bonilla E. Kearns-Sayre syndrome: oncocytic transformation of choroid plexus epithelium. J. Neurol. Sci. 2000;178:29–36.

    Article  CAS  PubMed  Google Scholar 

  88. Betts J, Jaros E, Perry RH, et al. Molecular neuropathology of MELAS: level of heteroplasmy in individual meurones and evidence of extensive vascular involvement. Neuropath Appl. Neurobiol. 2006;32:359–373.

    CAS  Google Scholar 

  89. Tanji K, Kunimatsu T, Vu TH, Bonilla E. Neuropathological features of mitochondrial disorders. Cell Develop. Biol. 2001;12:429–439.

    Article  CAS  Google Scholar 

  90. Sacconi S, Salviati L, Nishigaki Y, et al. A functionally dominant mitochondrial DNA mutation. Hum. Mol. Genet. 2008;17:1814–1820.

    Article  CAS  PubMed  Google Scholar 

  91. Schon EA, Santra S, Pallotti F, Girvin ME. Pathogenesis of primary defects in mitochondrial ATP synthesis. Cell Develop. Biol. 2001;12:441–448.

    Article  CAS  Google Scholar 

  92. Tatuch Y, Pagon RA, Vlcek B, et al. The 8993 mtDNA mutation: heteroplasmy and clinical presentation in three families. Eur. J. Hum. Genet. 1994.

    Google Scholar 

  93. Carrozzo R, Tessa A, Vazquez-Memije ME, et al. The T9176G mtDNA mutation affects ATP production and results in Leigh syndrome. Neurology 2001;56:687–690.

    CAS  PubMed  Google Scholar 

  94. Thyagarajan D, Shanske S, Vazquez-Memije M, et al. A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann. Neurol. 1995;38:468–472.

    Article  CAS  PubMed  Google Scholar 

  95. Vazquez-Memije ME, Shanske S, Santorelli FM, et al. Comparative biochemical studies of ATPases in cells from patients with the T8993G or T8993C mitochondrial DNA mutations. J. Inher. Metab. Dis. 1998;21:829–836.

    Article  CAS  PubMed  Google Scholar 

  96. Solaini G, Harris DA, Lenaz G, et al. The study of the pathogenic mechanism of mitochondrial diseases provides information on basic bioenergetics. Biochim. Biophys. Acta. 2008;1777:941–945.

    Article  CAS  PubMed  Google Scholar 

  97. Baracca A, Sgarbi G, Mattiazzi M, et al. Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993. Biochim. Biophys. Acta. 2007;1767:913–919.

    Article  CAS  Google Scholar 

  98. Pallotti F, Baracca A, Hernandez-Rosa E, et al. Biochemical analysis of respiratory function in cybrid cell lines harbouring mitochondrial DNA mutations. Biochem. J. 2004;384:287–293.

    Article  CAS  PubMed  Google Scholar 

  99. Carrozzo R, Murray J, Santorelli F, Capaldi RA. The T9176G mutation of human mtDNA gives fully assembled but inactive ATP synthase when modeled in Escherichia Coli. FEBS Lett. 2000;486:297–299.

    Article  CAS  PubMed  Google Scholar 

  100. Cortes-Hernandez P, Vazquez-Memije ME, Garcia JJ. ATP6 homoplasmic mutation inhibit and destabilize the human F1F0-ATP synthease without preventing enzyme assembly and oligomerization. J. Biol. Chem. 2007;282:1051–1058.

    Article  CAS  PubMed  Google Scholar 

  101. Garcia JJ, Ogilvie I, Robinson BH, Capaldi RA. Structure, function, and assembly of the ATP synthase in cells from patients with the T8993G mitochondrial DNA mutation. J. Biol. Chem. 2000;275:11075–11081.

    Article  CAS  PubMed  Google Scholar 

  102. Kirino Y, Yasukawa T, Ohta S, et al. Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. Proc. Natl. Acad. Sci. USA 2004;101:15070–15075.

    Article  CAS  PubMed  Google Scholar 

  103. Schon EA, Bonilla E, DiMauro S. Mitochondrial DNA mutations and pathogenesis. J. Bioenerg. Biomembr. 1997;29:131–149.

    Article  CAS  PubMed  Google Scholar 

  104. DiMauro S, Bonilla E, Mancuso M, et al. Mitochondrial myopathies. Basic Appl. Mol. 2003;13:145–155.

    Google Scholar 

  105. Taylor RW, Giordano C, Davidson MM, et al. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited cardiomyopathy. J. Am. Coll. Cardiol. 2003;41:1786–1796.

    Article  CAS  PubMed  Google Scholar 

  106. McFarland R, Schaefer AM, Gardner A, et al. Familial myopathy: New insights into the T14709C mitochondrial tRNA mutation. Ann. Neurol. 2004;55:478–484.

    Article  CAS  PubMed  Google Scholar 

  107. Shankar SP, Fingert JH, Carelli V, et al. Evidence for a novel X-linked modifier locus for Leber hereditary optic neuropathy. Opthal. Genet. 2008;29:17–24.

    Article  CAS  Google Scholar 

  108. Hudson G, Keers S, Man PYW, et al. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am. J. Hum. Genet. 2005;77:1086–1091.

    Article  CAS  PubMed  Google Scholar 

  109. Papadopoulou LC, Sue CM, Davidson MM, et al. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nature Genet. 1999;23:333–337.

    Article  CAS  PubMed  Google Scholar 

  110. Valnot I, Osmond S, Gigarel N, et al. Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am. J. Hum. Genet. 2000;67:1104–1109.

    CAS  PubMed  Google Scholar 

  111. Wallace DC. The mitochondrial genome in human adaptive radiation and disease: On the road to therapeutics and performance enhancement. Gene 2005;354:169–180.

    Article  CAS  PubMed  Google Scholar 

  112. Hudson G, Carelli V, Spruijt L, et al. Clinical expression of Leber Hereditary optic neuropahy is affected by the mitochondrial DNA-haplogroup background. Am. J. Hum. Genet. 2007;81:228–233.

    Article  CAS  PubMed  Google Scholar 

  113. Lodi R, Carelli V, Cortelli P, et al. Phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber’s hereditary optic neuropathy. J. Neurol. Neurosurg. Psychiat. 2002;72:805–807.

    Article  CAS  PubMed  Google Scholar 

  114. Cortelli P, Montagna P, Pierangeli G, et al. Clinical and brain bioenergetics improvement with idebenone in a patient with Leber’s hereditary optic neuropathy: a clinical amd 31P-MRS study. J. Neurol. Sci. 1997;148:25–31.

    Article  CAS  PubMed  Google Scholar 

  115. Valentino ML, Barboni P, Rengo C, et al. The 13042G>A/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype. J. Med. Genet. 2006;43:e38.

    Google Scholar 

  116. Barbiroli B, Iotti S, Lodi R. Improved brain and muscle mitochondrial respiration with CoQ. An in vivo study by 31P-MR spectroscopy in patients with mitochondrial cytopathies. BioFactors 1999;9:253–260.

    Article  CAS  PubMed  Google Scholar 

  117. Haller RG, Vissing J. Functional evaluation of metabolic myopathies. In: Engel AG, Franzini-Armstrong C, eds. Myology. Vol. 1. New York: McGraw-Hill, 2004:665–679.

    Google Scholar 

  118. Vazquez-Memije ME, Shanske S, Santorelli FM, et al. Comparative biochemical studies in fibroblasts from patients with different forms of Leigh syndrome. J. Inher. Metab. Dis. 1996;19:43–50.

    Article  CAS  PubMed  Google Scholar 

  119. Lenaz G, Baracca A, Carelli V, et al. Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim. Biophys. Acta. 2004;1658:89–94.

    Article  CAS  PubMed  Google Scholar 

  120. Baracca A, Barogi S, Carelli V, et al. Catalytic activities of mitochondrial ATP synthase in patients with mitochondrial DNA T8993G mutation in the ATPase 6 gene. J. Biol. Chem. 2000;275:4177–4182.

    Article  CAS  PubMed  Google Scholar 

  121. Baracca A, Solaini G, Sgarbi G, et al. Severe impairment of complex I-driven ATP synthesis in Leber’s hereditary optic neuropathy cybrids. Arch. Neurol. 2005;62:730–736.

    Article  PubMed  Google Scholar 

  122. Carelli V, Rugolo M, Sgarbi G, et al. Bioenergetics shapes cellular death pathways in Leber’s hereditary optic neuropathy: a model of mitochondrial neurodegeneration. Biochim. Biophys. Acta. 2004;1658:172–179.

    Article  CAS  PubMed  Google Scholar 

  123. Hirano M, DiMauro S. Leber’s hereditary optic neuropathy: biochemical lights in a blurry scenario. Arch. Neurol. 2005;62:711–712.

    Article  PubMed  Google Scholar 

  124. Droge W. Free radicals in the physiologycal control of cell function. Physiol. Rev. 2002;82:47–95.

    CAS  PubMed  Google Scholar 

  125. Verkaart S, Koopman WJH, van Emst-De Vries SE, et al. Superoxide production is inversely related to complex I activity in inherited complex I deficiency. Biochim. Biophys. Acta. 2007;1772:373–381.

    CAS  Google Scholar 

  126. Pitkanen S, Robinson BH. Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J. Clin. Invest. 1996;98:345–351.

    Article  CAS  PubMed  Google Scholar 

  127. Rimessi A, Giorgi C, Pinton P, Rizzuto R. The versatility of mitochondrial calcium signals: From stimulation of cell metabolism to induction of cell death. Biochim. Biophys. Acta. 2008;1777:808–816.

    Article  CAS  PubMed  Google Scholar 

  128. Brini M, Pinton P, King MP, et al. A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. Nature Med. 1999;5:951–954.

    Article  CAS  PubMed  Google Scholar 

  129. Moudy AM, Handran SD, Goldberg MP, et al. Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy. Proc. Natl. Acad. Sci. USA 1995;92:729–733.

    Article  CAS  PubMed  Google Scholar 

  130. Szadbadkai G, Simoni AM, Bianchi K, et al. Mitochondrial dynamics and Calcium signaling. Biochim. Biophys. Acta. 2006;1763:442–449.

    Article  CAS  Google Scholar 

  131. Bianchi K, Rimessi A, Prandini A, et al. Calcium and mitochondria: mechanisms and functions of a troubled relationship. Biochim. Biophys. Acta. 2004;1742:119–131.

    Article  CAS  PubMed  Google Scholar 

  132. DiMauro S, Hirano M, Schon EA. Approaches to the treatment of mitochondrial diseases. Muscle Nerve 2006;34:265–283.

    Article  CAS  PubMed  Google Scholar 

  133. Millhouse-Flourie TJ. Physical, occupational, respiratory, speech, equine, and pet therapies for mitochondrial disease. Mitochondrion 2004;4:549–558.

    Article  CAS  PubMed  Google Scholar 

  134. DiMauro S, Hirano M, Kaufmann P, Mann JJ. Mitochondrial psychiatry. In: DiMauro S, Hirano M, Schon EA, eds. Mitochondrial Medicine. London: Informa Healthcare, 2006:261–277.

    Google Scholar 

  135. Taivassalo T, Haller RG. Exercise and training in mitochondrial myopathies. Med. Sci. Sports Exerc. 2005;37:2094–2101.

    Article  CAS  PubMed  Google Scholar 

  136. Edmonds JL. Surgical and anesthetic management of patients with mitochondrial dysfunction. Mitochondrion 2004;4:543–548.

    Article  CAS  PubMed  Google Scholar 

  137. Sinnathurai AR, Raut V, Awa A, et al. A review of cochlear implantation in mitochondrial sensorineural hearing loss. Otolol. Neurol. 2003;24:418–426.

    Article  Google Scholar 

  138. Bonnet D, Rustin P, Rotig A, et al. Heart transplantation in children with mitochondrial cardiomyopathy. Heart 2001;86:570–573.

    Article  CAS  PubMed  Google Scholar 

  139. Lee WS, Sokol RJ. Mitochondrial hepatopathies: Advances in genetics and pathogenesis. Hepatology 2007;45:1555–1565.

    Article  CAS  PubMed  Google Scholar 

  140. Rotig A, Niaudet P. Mitochondrial nephrology. In: DiMauro S, Hirano M, Schon EA, eds. Mitochondrial Medicine. London: Informa Healthcare, 2006:197–207.

    Google Scholar 

  141. White SL, Shanske S, McGill JJ, et al. Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation. J. Inher. Metab. Dis. 1999;22:899–914.

    Article  CAS  PubMed  Google Scholar 

  142. Blok RB, Gook DA, Thorburn DR, Dahl H-HM. Skewed segregation of the mtDNA nt 8993 (T>G) mutation in human oocytes. Am. J. Hum. Genet. 1997;60:1495–1501.

    Article  CAS  PubMed  Google Scholar 

  143. Sato A, Kono T, Nakada K, et al. Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. Proc. Natl. Acad. Sci. USA 2005;102:16765–16770.

    Article  CAS  PubMed  Google Scholar 

  144. Hirano M, Marti R, Casali C, et al. Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology 2006;67:1458–1460.

    Article  CAS  PubMed  Google Scholar 

  145. Bastin J, Aubey F, Rotig A, et al. Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients’ cells lacking its components. J. Clin. Endocrinol. Metab. 2008;93:1433–1441.

    Article  CAS  PubMed  Google Scholar 

  146. Wenz T, Diaz F, Spiegelman BM, Moraes CT. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008;8:249–255.

    Article  CAS  PubMed  Google Scholar 

  147. Chinnery PF, Taylor RW, Diekert K, et al. Peptide nucleic acid delivery to human mitochondria. Gene Therapy 1999;6:1919–1928.

    Article  CAS  PubMed  Google Scholar 

  148. Taylor RW, Chinnery PF, Turnbull DM, Lightowlers RN. Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nature Genet. 1997;15:212–215.

    Article  CAS  PubMed  Google Scholar 

  149. Kolesnikova OA, Entelis NS, Jacquin-Becker C, et al. Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERF syndrome in cultured human cells. Hum. Mol. Genet. 2004;13:2519–2534.

    Article  CAS  PubMed  Google Scholar 

  150. Bai Y, Hajek P, Chomyn A, et al. Lack of complex I activity in human cells carrying a mutation in MtDNA-encoded ND4 subunit is corrected by the Saccharomyces cerevisiae NADH-quinone oxidoreductase (NDI1) gene. J. Biol. Chem. 2001;276:38808–38813.

    Article  CAS  PubMed  Google Scholar 

  151. Manfredi G, Fu J, Ojaimi J, et al. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nature Genet. 2002;30:394–399.

    Article  CAS  PubMed  Google Scholar 

  152. Bonnet C, Augustin S, Ellouze S, et al. The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochim. Biophys. Acta. 2008;1783:1707–1717.

    Article  CAS  PubMed  Google Scholar 

  153. Ellouze S, Augustin S, Bouaita A, et al. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am. J. Hum. Genet. 2008;83:373–387.

    Article  CAS  PubMed  Google Scholar 

  154. Hakkaart GA, Dassa EP, Jacobs HT, Rustin P. Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration. EMBO Rep. 2006;7:341–345.

    Article  CAS  PubMed  Google Scholar 

  155. Seo BB, Nakamura-Ogiso E, Flotte TR, et al. A single-subunit NADH-quinone oxidoreductase renders resistance to mammalian nerve cells against complex I inhibition. Mol. Ther. 2002;6:336–341.

    Article  CAS  PubMed  Google Scholar 

  156. Bacman SR, Williams SL, Hernandez D, Moraes CT. Modulating mtDNA heteroplasmy by mitochondria-targeted restriction endonucleases in a “differential multiple cleavage-site” model. Gene Ther. 2007;14:1309–1318.

    CAS  PubMed  Google Scholar 

  157. Tanaka M, Borgeld HJ, Zhang J, et al. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J. Biomed. Sci. 2002;9:534–541.

    CAS  PubMed  Google Scholar 

  158. Minczuk M, Papworth MA, Miller JG, et al. DEvelopment of a single-chain, quasi-dimeric zinc-finger nuclease for the selective degradation of mutated human mitochondrial DNA. Nucleic Acids Res. 2008;36:3926–3938.

    Article  CAS  PubMed  Google Scholar 

  159. Sabatini S, Kurtzman NA. Bicarbonate therapy in severe metabolic acidosis. J. Am. Soc. Nephrol. 2008;doi:10.1681/ASN.2007121329.

    Google Scholar 

  160. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989;38:1124–1144.

    Article  CAS  PubMed  Google Scholar 

  161. Stacpoole PW, Gilbert LR, Neiberger RE, et al. Evaluation of long-term treatment of children with congenital lactic cidosis with dichloroacetate. Pediatrics 2008;121:e1223-e1228.

    Article  PubMed  Google Scholar 

  162. Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 2006;117:1519–1531.

    Article  PubMed  Google Scholar 

  163. Felitsyn N, Stacpoole PW, Notterpek L. Dichloroacetate causes reversible demyelination in vitro: potential mechanism for its neuropathic effect. J. Neurochem. 2007;100:429–436.

    Article  CAS  PubMed  Google Scholar 

  164. Kaufmann P, Engelstad K, Wei Y-H, et al. Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial. Neurology 2006;66:324–330.

    Article  CAS  PubMed  Google Scholar 

  165. Kaufmann P, Anziska Y, Gooch CL, et al. Nerve conduction annormalities in MELAS/3243 patients. Arch. Neurol. 2006;63:746–748.

    Google Scholar 

  166. Spinazzola A, Marti R, Nishino I, et al. Altered thymidine metabolism due to defects of thymidine phosphorylase. J. Biol. Chem. 2002;277:4128–4132.

    Article  CAS  PubMed  Google Scholar 

  167. Quinzii C, Lopez de Munain A, Von-Moltke J, et al. Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency. FASEB J. 2008;in press.

    Google Scholar 

  168. Marriage BJ, Clandinin MT, Macdonald IM, Glerum DM. Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders. Mol. Genet. Metab. 2004;81:263–272.

    Article  CAS  PubMed  Google Scholar 

  169. Dougados M, Zitoun J, Laplane D, Castaigne P. Folate metabolism disorder in Kearns-Sayre syndrome. Ann. Neurol. 1983;13:687.

    Article  CAS  PubMed  Google Scholar 

  170. Allen RJ, DiMauro S, Coulter DL, et al. Kearns-Sayre syndrome with reduced plasma and cerebrospinal fluid folate. Ann Neurol. 1983;13:679–682.

    Article  CAS  PubMed  Google Scholar 

  171. Pineda M, Ormazabal A, Lopez-Gallardo E, et al. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann. Neurol. 2006;59:394–398.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  173. Klopstock T, Schlamp V, Schmidt F, et al. Creatine monohydrate in mitochondrial diseases: a double-blind, placebo-controlled, cross-over study in 16 patienrs with progressive external ophthalmoplegia or mitochondrial myopathy. Neurology 1999;52:A543-A544.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  175. Baker SK, Tarnopolsky MA. Targeting cellular energy production in neurological disorders. Expert Opin. Investig. Drugs. 2003;12:1–24.

    Article  Google Scholar 

  176. Di Prospero N, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007;6:878–886.

    Article  PubMed  CAS  Google Scholar 

  177. Naini A, Kaufmann P, Shanske S, et al. Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”. J. Neurol. Sci. 2005;229–230:187–193.

    Article  PubMed  CAS  Google Scholar 

  178. Koga Y, Akita Y, Nishioka J, et al. L-Arginine improves the symptoms of strokelike episodes in MELAS. Neurology 2005;64:710–712.

    Article  CAS  PubMed  Google Scholar 

  179. Koga Y, Akita Y, Junko N, et al. Endothelial dysfunction in MELAS improved by L-arginine supplementation. Neurology 2006;66:1766–1769.

    Article  CAS  PubMed  Google Scholar 

  180. Koga Y, Ishibashi M, Ueki I, et al. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology 2002;58:827–828.

    CAS  PubMed  Google Scholar 

  181. Kubota M, Sakakihara Y, Mori M, et al. Beneficial effect of L-arginine for stroke-like episode in MELAS. Brain Develop. 2004;26:481–483.

    Article  Google Scholar 

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Acknowledgements

Supported in part by NIH grant HD32062 and by the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF).

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  1. Department of Neurology, Columbia University Medical Center, 3-313 Russ Berrie Medical Science Pavilion, 10032, New York, NY, USA

    Salvatore DiMauro & Michio Hirano

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  1. CIBERER-BIOBANK, Avda. Campanar 21, Valencia, 46009, Spain

    Carmen Espinós

  2. Lab. Neurobiología, Centro de Investigación Príncipe Felipe, Av. Autopista del Saler 16, Valencia, 46012, Spain

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  3. Inst. Biomedicina, CSIC Valencia, C/ Jaime Roig 11, Valencia, 46010, Spain

    Francesc Palau

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DiMauro, S., Hirano, M. (2009). Pathogenesis and Treatment of Mitochondrial Disorders. In: Espinós, C., Felipo, V., Palau, F. (eds) Inherited Neuromuscular Diseases. Advances in Experimental Medicine and Biology, vol 652. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2813-6_10

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