Regulation of 2-Oxoglutarate (α-Ketoglutarate) Dehydrogenase Stability by the RING Finger Ubiquitin Ligase Siah

The 2-oxoglutarate dehydrogenase complex (OGHDC) (also known as the α-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-depend...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-12, Vol.279 (51), p.53782-53788
Main Authors: Habelhah, Hasem, Laine, Aaron, Erdjument-Bromage, Hediye, Tempst, Paul, Gershwin, M. Eric, Bowtell, David D.L., Ronai, Ze'ev
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Cell Line
Cytoplasm - metabolism
Electrophoresis, Polyacrylamide Gel
HeLa Cells
Humans
Immunoprecipitation
Ketoglutarate Dehydrogenase Complex - chemistry
Ketoglutarate Dehydrogenase Complex - physiology
Kinetics
Membrane Potentials
Mice
Microscopy, Fluorescence
Mitochondria - metabolism
Nuclear Proteins
Plasmids - metabolism
Proteasome Endopeptidase Complex - metabolism
Protein Binding
Protein Structure, Tertiary
Transcription Factors - metabolism
Transcription Factors - physiology
Transfection
Transgenes
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - chemistry
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Summary:The 2-oxoglutarate dehydrogenase complex (OGHDC) (also known as the α-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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M410315200