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J. Biol. Chem., Vol. 282, Issue 30, 21583-21587, July 27, 2007

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Cyclic AMP-dependent Protein Kinase Phosphorylation of Drp1 Regulates Its GTPase Activity and Mitochondrial Morphology^*

From the Cellular Neurology Unit, NINDS, National Institutes of Health, Bethesda, Maryland 20892

Mitochondria in cells comprise a tubulovesicular reticulum shaped by dynamic fission and fusion events. The multimeric dynamin-like GTPase Drp1 is a critical protein mediating mitochondrial division. It harbors multiple motifs including GTP-binding, middle, and GTPase effector (GED) domains that are important for both intramolecular and intermolecular interactions. As for other members of the dynamin superfamily, such interactions are critical for assembly of higher-order structures and cooperative increases in GTPase activity. Although the functions of Drp1 in cells have been extensively studied, mechanisms underlying its regulation remain less clear. Here, we have identified cAMP-dependent protein kinase-dependent phosphorylation of Drp1 within the GED domain at Ser⁶³⁷ that inhibits Drp1 GTPase activity. Mechanistically, this change in GTPase activity likely derives from decreased interaction of GTP-binding/middle domains with the GED domain since the phosphomimetic S637D mutation impairs this intramolecular interaction but not Drp1-Drp1 intermolecular interactions. Using the phosphomimetic S637D substitution, we also demonstrate that mitochondrial fission is prominently inhibited in cells. Thus, protein phosphorylation at Ser⁶³⁷ results in clear alterations in Drp1 function and mitochondrial morphology that are likely involved in dynamic regulation of mitochondrial division in cells.

Received for publication, April 27, 2007 Accepted for publication May 31, 2007.

^* This work was supported by the Intramural Research Program of the NINDS, 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ To whom correspondence should be addressed: Cellular Neurology Unit, NINDS, National Institutes of Health, Bldg. 35, Rm. 2C-913, 9000 Rockville Pike, Bethesda, MD 20892-3704. Tel.: 301-451-9680; Fax: 301-480-4888; E-mail: blackstc{at}ninds.nih.gov.

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