Alternative splicing isoform in succinate dehydrogenase complex, subunit C causes downregulation of succinate-coenzyme Q oxidoreductase activity in mitochondria

Satoh,Nana; Yokoyama,Chikako; Itamura,Noriaki; Miyajima‑Nakano,Yoshiharu; Hisatomi,Hisashi

doi:10.3892/ol.2014.2699

Alternative splicing isoform in succinate dehydrogenase complex, subunit C causes downregulation of succinate-coenzyme Q oxidoreductase activity in mitochondria

Authors:
- Nana Satoh
- Chikako Yokoyama
- Noriaki Itamura
- Yoshiharu Miyajima‑Nakano
- Hisashi Hisatomi
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Affiliations: Laboratory of Cellular and Molecular Biochemistry, Department of Materials and Life Science, Seikei Universty, Musashino, Tokyo 180‑8633, Japan
Published online on: November 11, 2014 https://doi.org/10.3892/ol.2014.2699
Pages: 330-334

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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, the SDHC Δ5 isoform (lacking exon 5) exhibits no SDHC activity. To investigate whether the SDHC splicing variants can function as dominant‑negative inhibitors, SDHC ASVs 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 on SDHC mRNA 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 the SDHC Δ5 variant may be significant for the differentiation of tumor cells.

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