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J. Biol. Chem., Vol. 283, Issue 12, 7580-7589, March 21, 2008

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Heat Shock Protein 90β1 Is Essential for Polyunsaturated Fatty Acid-induced Mitochondrial Ca²⁺ Efflux^*

From the Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, Audie L. Murphy Division, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229

Nonesterified fatty acids may influence mitochondrial function by alterations in gene expression, metabolism, and/or mitochondrial Ca²⁺ ([Ca²⁺]_m) homeostasis. We have previously reported that polyunsaturated fatty acids induce Ca²⁺ efflux from mitochondria, an action that may deplete [Ca²⁺]_m and thus contribute to nonesterified fatty acid-responsive mitochondrial dysfunction. Here we show that the chaperone protein heat shock protein 90 β1 (hsp90β1) is required for polyunsaturated fatty acid-induced mitochondrial Ca²⁺ efflux (PIMCE). Retinoic acid induced differentiation of human teratocarcinoma NT2 cells in association with attenuation of PIMCE. Proteomic analysis of mitochondrial proteins revealed that hsp90β1, among other proteins, was reduced in retinoic acid-differentiated cells. Blockade of PIMCE in NT2 cells by 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin, a known inhibitor of the chaperone activity of hsp90, and hsp90β1 RNA interference demonstrated that hsp90β1 is essential for PIMCE. We also show localization of hsp90β1 in mitochondria by Western blot and immunofluorescence. Distinctive effects of inhibitors binding to the N or C terminus of hsp90 on PIMCE in isolated mitochondria suggested that the C terminus of hsp90β1 plays a critical role in PIMCE.

Received for publication, August 27, 2007 , and in revised form, January 3, 2008.

^* This work was supported by American Heart Association Scientist Development Grant 0235065N and National Institutes of Health Grant HL075011 (to B. X. Z.). This work represents partial fulfillment of the requirements for the Ph.D. degree from the Fourth Military Medical University (H. Z.). 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 Figs. S1 and S2.

¹ To whom correspondence should be addressed: GRECC 182, South Texas Veterans Health Care System, Audie L. Murphy Division, 7400 Merton Minter Blvd., San Antonio, TX 78229. Tel.: 210-617-5197; Fax: 210-617-5312.

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