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J. Biol. Chem., Vol. 280, Issue 49, 40398-40401, December 9, 2005

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Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival^*

Junghee Lee, Chun-Hyung Kim¶, David K. Simon||, Lyaylya R. Aminova||, Alexander Y. Andreyev**, Yulia E. Kushnareva**, Anne N. Murphy**, Bonnie E. Lonze, Kwang-Soo Kim¶, David D. Ginty, Robert J. Ferrante1, Hoon Ryu12, and Rajiv R. Ratan

From the Neurology, Pathology, and Psychiatry Departments, Boston University School of Medicine, Boston, Massachusetts 02118, the Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, the ^¶Molecular Neurobiology Laboratory, McLean Hospital and ^||Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, ^**Mitochondrial Biology, MitoKor, San Diego, California 92121, the Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the Department of Neurology, Weill Medical College of Cornell University and Burke-Cornell Medical Research Institute, White Plains, New York 10605

Cyclic AMP response element-binding protein (CREB) is a widely expressed transcription factor whose role in neuronal protection is now well established. Here we report that CREB is present in the mitochondrial matrix of neurons and that it binds directly to cyclic AMP response elements (CREs) found within the mitochondrial genome. Disruption of CREB activity in the mitochondria decreases the expression of a subset of mitochondrial genes, including the ND5 subunit of complex I, down-regulates complex I-dependent mitochondrial respiration, and increases susceptibility to 3-nitropropionic acid, a mitochondrial toxin that induces a clinical and pathological phenotype similar to Huntington disease. These results demonstrate that regulation of mitochondrial gene expression by mitochondrial CREB, in part, underlies the protective effects of CREB and raise the possibility that decreased mitochondrial CREB activity contributes to the mitochondrial dysfunction and neuronal loss associated with neurodegenerative disorders.

Received for publication, March 28, 2005 , and in revised form, September 23, 2005.

^* This work was supported by National Institutes of Health Grants NS52724-01 (to H. R.), P30 AG13846 (to J. L.), MH48866 (to K.-S. K.), NS045242 and NS045806 (to R. J. F.), and NS39170 and NS40591 (to R. R. R.); by the High Q Foundation and the Huntington Disease Society of America (to H. R. and R. J. F.); and by the Veterans Administration (to R. J. F. and J. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental methods, references, and Figs. 1-7 and Tables 1 and 2.

¹ Grant awardees of the Jerry McDonald Huntington Disease Foundation from Boston University School of Medicine.

² To whom correspondence should be addressed: GRECC 18B, Bedford Veterans Affairs Medical Center, 200 Springs Rd., Bedford, MA 01730. Tel.: 781-687-2922; Fax: 781-687-3515; E-mail: hoonryu{at}bu.edu.

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