title: hMTH1 expression protects mitochondria from Huntington's disease-like impairment.
abstract: 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 (Hdh(Q111)). 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 Hdh(Q111) 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.
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Ventura
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Russo
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Nuccio
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: De Luca
authors.affiliation: Department of Epidemiology, Prevention and Special Function, Istituto Nazionale per la Ricerca sul Cancro, Lgo Rosanna Benzi 10, 16123 Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Degan
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Bernardo
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Visentin
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Electronic address: luisa.minghetti@iss.it.
authors.forename: Luisa
authors.initials: L
authors.lastname: Minghetti
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Electronic address: margherita.bignami@iss.it.
authors.forename: Margherita
authors.initials: M
authors.lastname: Bignami
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011422:Propionates / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes; C015392:3-nitropropionic acid