HMTH1 expression protects mitochondria from Huntington's disease-like impairment

Ilenia Ventura, Maria Teresa Russo, Chiara De Nuccio, Gabriele De Luca, Paolo Degan, Antonietta Bernardo, Sergio Visentin, Luisa Minghetti, Margherita Bignami

Research output: Contribution to journalArticlepeer-review


Huntington disease (HD) is a neurodegenerative disease caused by expansion of CAG repeats in the huntingtin (Htt) gene. The expression of hMTH1, the human hydrolase that degrades oxidized purine nucleoside triphosphates, grants protection in a chemical HD mouse model in which HD-like features are induced by the mitochondrial toxin 3-nitropropionic acid (3-NP). To further examine the relationship between oxidized dNTPs and HD-like neurodegeneration, we studied the effects of hMTH1 expression in a genetic cellular model for HD, such as striatal cells expressing mutant htt (HdhQ111). hMTH1 expression protected these cells from 3-NP and H2O2-induced killing, by counteracting the mutant htt-dependent increased vulnerability and accumulation of nuclear and mitochondrial DNA 8-hydroxyguanine levels. hMTH1 expression reverted the decreased mitochondrial membrane potential characteristic of HdhQ111 cells and delayed the increase in mitochondrial reactive oxygen species associated with 3-NP treatment. Further indications of hMTH1-mediated mitochondrial protection are the partial reversion of 3-NP-induced alterations in mitochondrial morphology and the modulation of DRP1 and MFN1 proteins, which control fusion/fission rates of mitochondria. Finally, in line with the in vitro findings, upon 3-NP in vivo treatment, 8-hydroxyguanine levels in mitochondrial DNA from heart, muscle and brain are significantly lower in transgenic hMTH1-expressing mice than in wild-type animals.

Original languageEnglish
Pages (from-to)148-158
Number of pages11
JournalNeurobiology of Disease
Issue number1
Publication statusPublished - Jan 2013


  • 8-hydroxyguanine
  • HMTH1
  • Mitochondria
  • Oxidative stress

ASJC Scopus subject areas

  • Neurology


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