title: Dysregulation of mitochondrial calcium signaling and superoxide flashes cause mitochondrial genomic DNA damage in Huntington disease.
abstract: Huntington disease (HD) is an inherited, fatal neurodegenerative disorder characterized by the progressive loss of striatal medium spiny neurons. Indications of oxidative stress are apparent in brain tissues from both HD patients and HD mouse models; however, the origin of this oxidant stress remains a mystery. Here, we used a yeast artificial chromosome transgenic mouse model of HD (YAC128) to investigate the potential connections between dysregulation of cytosolic Ca(2+) signaling and mitochondrial oxidative damage in HD cells. We found that YAC128 mouse embryonic fibroblasts exhibit a strikingly higher level of mitochondrial matrix Ca(2+) loading and elevated superoxide generation compared with WT cells, indicating that both mitochondrial Ca(2+) signaling and superoxide generation are dysregulated in HD cells. The excessive mitochondrial oxidant stress is critically dependent on mitochondrial Ca(2+) loading in HD cells, because blocking mitochondrial Ca(2+) uptake abolished elevated superoxide generation. Similar results were obtained using neurons from HD model mice and fibroblast cells from HD patients. More importantly, mitochondrial Ca(2+) loading in HD cells caused a 2-fold higher level of mitochondrial genomic DNA (mtDNA) damage due to the excessive oxidant generation. This study provides strong evidence to support a new causal link between dysregulated mitochondrial Ca(2+) signaling, elevated mitochondrial oxidant stress, and mtDNA damage in HD. Our results also indicate that reducing mitochondrial Ca(2+) uptake could be a therapeutic strategy for HD.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiu-Qiang
authors.initials: JQ
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
authors.forename: Qiao-Chu
authors.initials: QC
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: He-Ping
authors.initials: HP
authors.lastname: Cheng
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
authors.forename: Qinmiao
authors.initials: Q
authors.lastname: Sun
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Tie-Shan
authors.initials: TS
authors.lastname: Tang
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D004249:DNA Damage / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054629:Genome, Mitochondrial / Q000235:genetics*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017072:Neostriatum / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012118:Resorcinols / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D004272:DNA, Mitochondrial; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012118:Resorcinols; C034703:mitochondrial calcium uniporter; D013481:Superoxides; C079215:3,5-dihydroxyphenylglycine; D001920:Bradykinin; D002118:Calcium; D005998:Glycine