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J. Biol. Chem., Vol. 279, Issue 51, 53782-53788, December 17, 2004

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Regulation of 2-Oxoglutarate (-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||, and Ze'ev Ronai**

From the Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021, ^¶Division of Rheumatology, Allergy, and Clinical Immunology, University of California School of Medicine, Davis, California 95616, and ^||MacCallum Cancer Institute, Melbourne 3002, Victoria, Australia

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

Received for publication, September 8, 2004 , and in revised form, October 5, 2004.

^* This work was supported by NCI Grant CA78419 (to Z. R.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Oncological Sciences, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1130, New York, NY 10029. Tel.: 212-659-5571; Fax: 212-849-2425. E-mail: zeev.ronai{at}mssm.edu; or ronai{at}burnham.org.

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