title: Alternative splicing isoform in succinate dehydrogenase complex, subunit C causes downregulation of succinate-coenzyme Q oxidoreductase activity in mitochondria.
abstract: Mitochondrial succinate dehydrogenase (SDH) is localized to the inner mitochondrial membrane and is responsible for the redox of succinic acid. SDH is a tetrameric iron-sulfur flavoprotein of the tricarboxylic acid cycle and respiratory chain. The SDH complex, subunit C (SDHC) transcript has deletion-type alternative splicing sites. Generally, alternative splicing produces variant proteins and expression patterns, as products of different genes. In certain cases, specific alternative splicing variants (ASVs) have been associated with human disease. Due to a frameshift mutation causing loss of the heme binding region, theSDHCΔ5 isoform (lacking exon 5) exhibits no SDHC activity. To investigate whether theSDHCsplicing variants can function as dominant-negative inhibitors,SDHCASVs were overexpressed in HCT-15 human colorectal cancer cells. Using real-time reverse transcription-polymerase chain reaction, a dominant-negative effect of the Δ5 isoform onSDHCmRNA was shown. In addition, Δ5 overexpression increased the levels of reactive oxygen species. Furthermore, in the Δ5 isoform-overexpressing cells, SDH activity was reduced. SDHC activation is a significant event during the electron transport chain, and the function of theSDHCΔ5 variant may be significant for the differentiation of tumor cells.
authors.affiliation: Laboratory of Cellular and Molecular Biochemistry, Department of Materials and Life Science, Seikei Universty, Musashino, Tokyo 180-8633, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Satoh
authors.affiliation: Laboratory of Cellular and Molecular Biochemistry, Department of Materials and Life Science, Seikei Universty, Musashino, Tokyo 180-8633, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Yokoyama
authors.affiliation: Laboratory of Cellular and Molecular Biochemistry, Department of Materials and Life Science, Seikei Universty, Musashino, Tokyo 180-8633, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Itamura
authors.affiliation: Laboratory of Cellular and Molecular Biochemistry, Department of Materials and Life Science, Seikei Universty, Musashino, Tokyo 180-8633, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Miyajima-Nakano
authors.affiliation: Laboratory of Cellular and Molecular Biochemistry, Department of Materials and Life Science, Seikei Universty, Musashino, Tokyo 180-8633, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hisatomi
keywords: alternative splicing; dominant-negative inhibitor; subunit C; succinate dehydrogenase complex