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 journalArticlepeer-review

44 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry

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