title: Enhanced metallothionein gene expression induced by mitochondrial oxidative stress is reduced in phospholipid hydroperoxide glutathione peroxidase-overexpressed cells.
abstract: Mitochondria are major compartments in cells responsible for generating reactive oxygen species, which can cause the development of diabetes, Parkinson's disease and premature aging. Antioxidant systems in mitochondria are important for the prevention of diseases and reduction in the speed of aging. We investigated whether the reactive oxygen species generated in mitochondria induced the expression of metallothionein as an antioxidant. We compared the expression level of metallothionein mRNA in mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx)-overexpressed (PHGPx-ov) cells with that in control cells. These cells were treated with respiratory inhibitors, including rotenone and 2, 4-dinitrophenol; under these conditions, the PHGPx-ov cells were more resistant to cell death than the control cells. In addition, the intracellular reactive oxygen species level that was induced by these inhibitors was lower in PHGPx-ov cells than in control cells. This indicates that PHGPx degrades the membrane phospholipid hydroperoxide that is formed via the reactive oxygen species generated in mitochondria. The enhanced expression of metallothionein-I and metallothionein-II mRNA in rotenone-treated control cells was significantly decreased in rotenone-treated PHGPx-ov cells, suggesting that the hydrogen peroxide that is formed by superoxide anions generated in mitochondria diffuse into the cytosol and induce metallothionein mRNA expression. Conversely, the expression of manganese-superoxide dismutase (Mn-SOD) mRNA, which is localized in mitochondria, was not correlated with the intracellular reactive oxygen species level that was induced by rotenone treatment. These results suggest that metallothionein expression is sensitively and strictly regulated by the oxidative state that is induced by mitochondrial respiration.
authors.affiliation: Tokushima Bunri University, 180 Yamashiro-cho, Tokushima 770-8514, Japan. ykadota@ph.bunri-u.ac.jp
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kadota
authors.forename: Shinya
authors.initials: S
authors.lastname: Suzuki
authors.forename: Seiko
authors.initials: S
authors.lastname: Ideta
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fukinbara
authors.forename: Takashige
authors.initials: T
authors.lastname: Kawakami
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imai
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Masao
authors.initials: M
authors.lastname: Sato
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012402:Rotenone; D008668:Metallothionein; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D019297:2,4-Dinitrophenol