Regulation of 2-oxoglutarate (α-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase siah

Hasem Habelhah, Aaron Laine, Hediye Erdjument-Bromage, Paul Tempst, M. Eric Gershwin, David D L Bowtell, Ze'ev Ronai

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)53782-53788
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number51
DOIs
StatePublished - Dec 17 2004
Externally publishedYes

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Ketoglutarate Dehydrogenase Complex
Ligases
Ubiquitin
Oxidoreductases
Degradation
Mitochondria
Ubiquitin-Protein Ligases
Citric Acid Cycle
Mitochondrial Membrane Potential
Ubiquitination
Proteasome Endopeptidase Complex
Cytoplasm
Membranes
Enzymes
alpha-ketoglutaric acid

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of 2-oxoglutarate (α-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase siah. / Habelhah, Hasem; Laine, Aaron; Erdjument-Bromage, Hediye; Tempst, Paul; Gershwin, M. Eric; Bowtell, David D L; Ronai, Ze'ev.

In: Journal of Biological Chemistry, Vol. 279, No. 51, 17.12.2004, p. 53782-53788.

Research output: Contribution to journalArticle

Habelhah, Hasem ; Laine, Aaron ; Erdjument-Bromage, Hediye ; Tempst, Paul ; Gershwin, M. Eric ; Bowtell, David D L ; Ronai, Ze'ev. / Regulation of 2-oxoglutarate (α-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase siah. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 51. pp. 53782-53788.
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AU - Tempst, Paul

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AU - Bowtell, David D L

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AB - 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.

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