Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah.

The 2-oxoglutarate dehydrogenase complex (OGHDC) (also known as the alpha-ketoglutarate dehydrogenase complex) is a rate-limiting enzyme in the mitochondrial Krebs cycle. Here we report that the RING finger ubiquitin-protein isopeptide ligase Siah2 binds to and targets OGDHC-E2 for ubiquitination-dependent degradation. OGDHC-E2 expression and activity are elevated in Siah2(-/-) cells compared ...
with Siah2(+)(/)(+) cells. Deletion of the mitochondrial targeting sequence of OGDHC-E2 results in its cytoplasmic localization and rapid proteasome-dependent degradation in Siah2(+)(/)(+) but not in Siah2(-/-) cells. Significantly, because of its overexpression or disruption of the mitochondrial membrane potential, the release of OGDHC-E2 from mitochondria to the cytoplasm also results in its concomitant degradation. The role of the Siah family of ligases in the regulation of OGDHC-E2 stability is expected to take place under pathological conditions in which the levels of OGDHC-E2 are altered.
Mesh Terms:
Animals, Blotting, Western, Cell Line, Cytoplasm, Electrophoresis, Polyacrylamide Gel, Hela Cells, Humans, Immunoprecipitation, Ketoglutarate Dehydrogenase Complex, Kinetics, Membrane Potentials, Mice, Microscopy, Fluorescence, Mitochondria, Nuclear Proteins, Plasmids, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Tertiary, Transcription Factors, Transfection, Transgenes, Ubiquitin, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Dec. 17, 2004
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