Journal of Molecular Medicine

, Volume 88, Issue 4, pp 431–436 | Cite as

Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington disease

  • Larissa Arning
  • Aiden Haghikia
  • Elahe Taherzadeh-Fard
  • Carsten Saft
  • Jürgen Andrich
  • Bartoz Pula
  • Stefan Höxtermann
  • Stefan Wieczorek
  • Denis Amer Akkad
  • Moritz Perrech
  • Ralf Gold
  • Jörg Thomas Epplen
  • Andrew Chan
Original article


Mitochondrial dysfunction has been implicated in the pathogenesis of Huntington disease (HD), a primarily neurodegenerative disorder that results from an expansion in the polymorphic trinucleotide CAG tract in the HD gene. In order to evaluate whether mitochondrial DNA (mtDNA) variation contributes to HD phenotype we genotyped 13 single nucleotide polymorphisms (SNPs) that define the major European mtDNA haplogroups in 404 HD patients. Genotype-dependent functional effects on intracellular ATP concentrations were assessed in peripheral leukocytes. In patients carrying the most common haplogroup H (48.3%), we demonstrate a significantly lower age at onset (AO). In combination with PGC-1alpha genotypes, 3.8% additional residual variance in HD AO can be explained. Intracellular ATP concentrations in HD patients carrying the cytochrome c oxidase subunit I (CO1) 7028C allele defining haplogroup H were significantly higher in comparison to non-H individuals (mean ± SEM, 599 ± 51.8 ng/ml, n = 14 vs. 457.5 ± 40.4 ng/ml, p = 0.03, n = 9). In contrast, ATP concentrations in cells of HD patients independent from mtDNA haplogroup showed no significant differences in comparison to matched healthy controls. Our data suggest that an evolutionarily advantageous mitochondrial haplogroup is associated with functional mitochondrial alterations and may modify disease phenotype in the context of neurodegenerative conditions such as HD.


Huntington disease Age at onset mtDNA haplogroups ATP 


Conflict of interest statement

The authors declare that they have no conflicts of interest.


  1. 1.
    The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRefGoogle Scholar
  2. 2.
    Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P, MacDonald ME, Gusella JF, Harper PS, Shaw DJ (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat Genet 4:393–397CrossRefPubMedGoogle Scholar
  3. 3.
    Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA et al (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4:398–403CrossRefPubMedGoogle Scholar
  4. 4.
    Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M et al (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392CrossRefPubMedGoogle Scholar
  5. 5.
    Andresen JM, Gayán J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA; US-Venezuela Collaborative Research Group, Cardon LR, Housman DE, Wexler NS (2007) Replication of twelve association studies for Huntington’s disease residual age of onset in large Venezuelan kindreds. J Med Genet 44:44–50Google Scholar
  6. 6.
    Arning L, Saft C, Wieczorek S, Andrich J, Kraus PH, Epplen JT (2007) NR2A and NR2B receptor gene variations modify age at onset in Huntington disease in a sex-specific manner. Hum Genet 122:175–182CrossRefPubMedGoogle Scholar
  7. 7.
    Arning L, Monté D, Hansen W, Wieczorek S, Jagiello P, Akkad DA, Andrich J, Kraus PH, Saft C, Epplen JT (2008) ASK1 and MAP2K6 as modifiers of age at onset in Huntington’s disease. J Mol Med 86:485–490CrossRefPubMedGoogle Scholar
  8. 8.
    Metzger S, Rong J, Nguyen HP, Cape A, Tomiuk J, Soehn AS, Propping P, Freudenberg-Hua Y, Freudenberg J, Tong L et al (2008) Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington’s disease. Hum Mol Genet 17:1137–1146CrossRefPubMedGoogle Scholar
  9. 9.
    Gusella JF, Macdonald ME (2009) Huntington’s disease: the case for genetic modifiers. Genome Med 8:80CrossRefGoogle Scholar
  10. 10.
    Weydt P, Soyal SM, Gellera C, Didonato S, Weidinger C, Oberkofler H, Landwehrmeyer GB, Patsch W (2009) The gene coding for PGC-1alpha modifies age at onset in Huntington’s disease. Mol Neurodegener 4:3CrossRefPubMedGoogle Scholar
  11. 11.
    Taherzadeh-Fard E, Saft C, Andrich J, Wieczorek S, Arning L (2009) PGC-1 alpha as modifier of onset age in Huntington disease. Mol Neurodegener 4:10CrossRefPubMedGoogle Scholar
  12. 12.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795CrossRefPubMedGoogle Scholar
  13. 13.
    Bossy-Wetzel E, Petrilli A, Knott AB (2008) Mutant huntingtin and mitochondrial dysfunction. Trends Neurosci 31:609–616CrossRefPubMedGoogle Scholar
  14. 14.
    Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR (1993) Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology 43:2689–2695PubMedGoogle Scholar
  15. 15.
    Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Warner TT (2000) Abnormal in vivo skeletal muscle energy metabolism in Huntington’s disease and dentatorubropallidoluysian atrophy. Ann Neurol 48:72–76CrossRefPubMedGoogle Scholar
  16. 16.
    Saft C, Zange J, Andrich J, Müller K, Lindenberg K, Landwehrmeyer B, Vorgerd M, Kraus PH, Przuntek H, Schöls L (2005) Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington’s disease. Mov Disord 20:674–679CrossRefPubMedGoogle Scholar
  17. 17.
    Aziz NA, van der Burg JM, Landwehrmeyer GB, Brundin P, Stijnen T; EHDI Study Group, Roos RA (2008) Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 71:1506–1513CrossRefGoogle Scholar
  18. 18.
    Wallace DC, Brown MD, Lott MT (1999) Mitochondrial DNA variation in human evolution and disease. Gene 238:211–230CrossRefPubMedGoogle Scholar
  19. 19.
    Niemi AK, Moilanen JS, Tanaka M, Hervonen A, Hurme M, Lehtimäki T, Arai Y, Hirose N, Majamaa K (2005) A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects. Eur J Hum Genet 13:166–170CrossRefPubMedGoogle Scholar
  20. 20.
    van der Walt JM, Nicodemus KK, Martin ER, Scott WK, Nance MA, Watts RL, Hubble JP, Haines JL, Koller WC, Lyons K et al (2003) Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 72:804–811CrossRefPubMedGoogle Scholar
  21. 21.
    van der Walt JM, Dementieva YA, Martin ER et al (2004) Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 365:28–32CrossRefPubMedGoogle Scholar
  22. 22.
    Takasaki S (2008) Mitochondrial SNPs associated with Japanese centenarians, Alzheimer’s patients, and Parkinson’s patients. Comput Biol Chem 32:332–337CrossRefPubMedGoogle Scholar
  23. 23.
    Vogler S, Goedde R, Miterski B, Gold R, Kroner A, Koczan D, Zettl UK, Rieckmann P, Epplen JT, Ibrahim SM (2005) Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. J Mol Med 83:806–811CrossRefPubMedGoogle Scholar
  24. 24.
    Arning L, Kraus PH, Valentin S, Saft C, Andrich J, Epplen JT (2005) NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics 6:25–28CrossRefPubMedGoogle Scholar
  25. 25.
    Wiesbauer M, Meierhofer D, Mayr JA, Sperl W, Paulweber B, Kofler B (2006) Multiplex primer extension analysis for rapid detection of major European mitochondrial haplogroups. Electrophoresis 27:3864–3868CrossRefPubMedGoogle Scholar
  26. 26.
    Rosa A, Fonseca BV, Krug T, Manso H, Gouveia L, Albergaria I, Gaspar G, Correia M, Viana-Baptista M, Simões RM et al (2008) Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients. BMC Med Genet 9:57CrossRefPubMedGoogle Scholar
  27. 27.
    Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5:731–736PubMedGoogle Scholar
  28. 28.
    Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler JF Jr, Greenamyre JT, Snyder SH, Ross CA (1999) Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat Med 5:1194–1198CrossRefPubMedGoogle Scholar
  29. 29.
    Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M et al (2005) HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet 14:2871–2880CrossRefPubMedGoogle Scholar
  30. 30.
    Baudouin SV, Saunders D, Tiangyou W, Elson JL, Poynter J, Pyle A, Keers S, Turnbull DM, Howell N, Chinnery PF (2005) Mitochondrial DNA and survival after sepsis: a prospective study. Lancet 366:2118–2121CrossRefPubMedGoogle Scholar
  31. 31.
    Hendrickson SL, Hutcheson HB, Ruiz-Pesini E, Poole JC, Lautenberger J, Sezgin E, Kingsley L, Goedert JJ, Vlahov D, Donfield S et al (2008) Mitochondrial DNA haplogroups influence AIDS progression. AIDS 22:2429–2439CrossRefPubMedGoogle Scholar
  32. 32.
    Brand MD (2000) Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35:811–820CrossRefPubMedGoogle Scholar
  33. 33.
    Mancuso M, Kiferle L, Petrozzi L, Nesti C, Rocchi A, Ceravolo R, Orsucci D, Maluccio MR, Bonuccelli U, Filosto M et al (2008) Mitochondrial DNA haplogroups do not influence the Huntington’s disease phenotype. Neurosci Lett 444:83–86CrossRefPubMedGoogle Scholar
  34. 34.
    De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, Bonafe M, Monti D, Baggio G, Bertolini S et al (1999) Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J 13:1532–1536PubMedGoogle Scholar
  35. 35.
    Rose G, Passarino G, Carrieri G, Altomare K, Greco V, Bertolini S, Bonafè M, Franceschi C, De Benedictis G (2001) Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians. Eur J Hum Genet 9:701–707CrossRefPubMedGoogle Scholar
  36. 36.
    Niemi AK, Hervonen A, Hurme M, Karhunen PJ, Jylhä M, Majamaa K (2003) Mitochondrial DNA polymorphisms associated with longevity in a Finnish population. Hum Genet 112:29–33CrossRefPubMedGoogle Scholar
  37. 37.
    Ghezzi D, Marelli C, Achilli A, Goldwurm S, Pezzoli G, Barone P, Pellecchia MT, Stanzione P, Brusa L, Bentivoglio AR et al (2005) Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson’s disease in Italians. Eur J Hum Genet 13:748–752CrossRefPubMedGoogle Scholar
  38. 38.
    Ruiz-Pesini E, Lapeña AC, Díez-Sánchez C, Pérez-Martos A, Montoya J, Alvarez E, Díaz M, Urriés A, Montoro L, López-Pérez MJ et al (2000) Human mtDNA haplogroups associated with high or reduced spermatozoa motility. Am J Hum Genet 67:682–696CrossRefPubMedGoogle Scholar
  39. 39.
    Bellizzi D, Cavalcante P, Taverna D, Rose G, Passarino G, Salvioli S, Franceschi C, De Benedictis G (2006) Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in ybrid cell lines. Genes Cells 11:883–891CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Larissa Arning
    • 1
  • Aiden Haghikia
    • 2
  • Elahe Taherzadeh-Fard
    • 1
  • Carsten Saft
    • 2
  • Jürgen Andrich
    • 2
  • Bartoz Pula
    • 2
  • Stefan Höxtermann
    • 3
  • Stefan Wieczorek
    • 1
  • Denis Amer Akkad
    • 1
  • Moritz Perrech
    • 2
  • Ralf Gold
    • 2
  • Jörg Thomas Epplen
    • 1
  • Andrew Chan
    • 2
  1. 1.Department of Human GeneticsRuhr-UniversityBochumGermany
  2. 2.Department of Neurology, St. Josef HospitalRuhr-UniversityBochumGermany
  3. 3.Department of Dermatology, St. Josef HospitalRuhr-UniversityBochumGermany

Personalised recommendations