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J. Biol. Chem., Vol. 283, Issue 16, 10967-10977, April 18, 2008

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Transcriptional Regulation of SDHa Flavoprotein by Nuclear Respiratory Factor-1 Prevents Pseudo-hypoxia in Aerobic Cardiac Cells^*

Claude A. Piantadosi¹ and Hagir B. Suliman

From the Departments of Medicine and Anesthesiology, Duke University School of Medicine and the Durham Veteran's Administration Medical Center, Durham, North Carolina 27710

Nuclear respiratory factor-1 (NRF-1) is integral to the transcriptional regulation of mitochondrial biogenesis, but its control over various respiratory genes overlaps other regulatory elements including those involved in O₂ sensing. Aerobic metabolism generally suppresses hypoxia-sensitive genes, e.g. via hypoxia-inducible factor-1 (HIF-1), but mutations in Complex II-succinate dehydrogenase (SDH), a tumor suppressor, stabilize HIF-1, producing pseudo-hypoxia. In aerobic cardiomyocytes, which rely on oxidative phosphorylation, we tested the hypothesis that NRF-1 regulates Complex II expression and opposes hypoxia-inducible factor-1. NRF-1 gene silencing blocked aerobic succinate oxidation, increasing nuclear HIF-1 protein prior to the loss of Complex I function. We postulated that NRF-1 suppression either specifically decreases the expression of one or more SDH subunits and increases succinate availability to regulate HIF-1 prolyl hydroxylases, or stimulates mitochondrial reactive oxygen production, which interferes with HIF-1 degradation. Using promoter analysis, gene silencing, and chromatin immunoprecipitation, NRF-1 was found to bind to the gene promoters of two of four nuclear-encoded Complex II subunits: SDHa and SDHd, but the enzyme activity was dynamically regulated through the catalytic SDHa flavoprotein. Complex II was inactivated by SDHa silencing, which led to aerobic HIF-1 stabilization, nuclear translocation, and enhanced expression of glucose transporters and heme oxygenase-1. This was unrelated to mitochondrial ROS production, reversible by high -ketoglutarate concentrations, and coherent with regulation of HIF-1 by succinate reported in tumor cells. These findings disclose a novel role for NRF-1 in the transcriptional control of Complex II and prevention of pseudo-hypoxic gene expression in aerobic cardiac cells.

Received for publication, November 28, 2007 , and in revised form, February 4, 2008.

^* This work was supported in part by NHLBI, National Institutes of Health Grant P01 42-444 and a grant from the Veteran's Administration (to C. A. P.). 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.

¹ To whom correspondence should be addressed: CR II Bldg., Box 3315, Duke University Medical Center, Durham, NC 27710. Fax 919-684-6002; E-mail: piant001{at}mc.duke.edu.

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