title: Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin.
abstract: Huntington disease (HD) is an inherited neurodegenerative disease resulting from an abnormal expansion of polyglutamine in huntingtin (Htt). Compromised oxidative stress defense systems have emerged as a contributing factor to the pathogenesis of HD. Indeed activation of the Nrf2 pathway, which plays a prominent role in mediating antioxidant responses, has been considered as a therapeutic strategy for the treatment of HD. Given the fact that there is an interrelationship between impairments in mitochondrial dynamics and increased oxidative stress, in this present study we examined the effect of mutant Htt (mHtt) on these two parameters. STHdh(Q111/Q111) cells, striatal cells expressing mHtt, display more fragmented mitochondria compared to STHdh(Q7/Q7) cells, striatal cells expressing wild type Htt, concurrent with alterations in the expression levels of Drp1 and Opa1, key regulators of mitochondrial fission and fusion, respectively. Studies of mitochondrial dynamics using cell fusion and mitochondrial targeted photo-switchable Dendra revealed that mitochondrial fusion is significantly decreased in STHdh(Q111/Q111) cells. Oxidative stress leads to dramatic increases in the number of STHdh(Q111/Q111) cells containing swollen mitochondria, while STHdh(Q7/Q7) cells just show increases in the number of fragmented mitochondria. mHtt expression results in reduced activity of Nrf2, and activation of the Nrf2 pathway by the oxidant tBHQ is significantly impaired in STHdh(Q111/Q111) cells. Nrf2 expression does not differ between the two cell types, but STHdh(Q111/Q111) cells show reduced expression of Keap1 and p62, key modulators of Nrf2 signaling. In addition, STHdh(Q111/Q111) cells exhibit increases in autophagy, whereas the basal level of autophagy activation is low in STHdh(Q7/Q7) cells. These results suggest that mHtt disrupts Nrf2 signaling which contributes to impaired mitochondrial dynamics and may enhance susceptibility to oxidative stress in STHdh(Q111/Q111) cells.
authors.affiliation: Departmentsof Pharmacology and Physiology, University of Rochester, Rochester, New York, United States of America.
authors.forename: Youngnam N
authors.initials: YN
authors.lastname: Jin
authors.forename: Yanxun V
authors.initials: YV
authors.lastname: Yu
authors.forename: Soner
authors.initials: S
authors.lastname: Gundemir
authors.forename: Chulman
authors.initials: C
authors.lastname: Jo
authors.forename: Mei
authors.initials: M
authors.lastname: Cui
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008156:Luciferases; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics*; D009154:Mutation; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C485120:Nrf3 protein, mouse; D009687:Nuclear Proteins; D008156:Luciferases; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins