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Mol. Cell. Biol. 25 (19): 8520-8530

Copyright © 2005 by the American Society for Microbiology. All rights reserved.

Protein Kinase D Mediates Mitochondrion-to-Nucleus Signaling and Detoxification from Mitochondrial Reactive Oxygen Species{dagger}

Peter Storz,{ddagger} Heike Döppler,, and Alex Toker*

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215

Received for publication 15 March 2005. Revision received 27 April 2005. Accepted for publication 14 July 2005.

Abstract: Efficient elimination of mitochondrial reactive oxygen species (mROS) correlates with increased cellular survival and organism life span. Detoxification of mitochondrial ROS is regulated by induction of the nuclear SOD2 gene, which encodes the manganese-dependent superoxide dismutase (MnSOD). However, the mechanisms by which mitochondrial oxidative stress activates cellular signaling pathways leading to induction of nuclear genes are not known. Here we demonstrate that release of mROS activates a signal relay pathway in which the serine/threonine protein kinase D (PKD) activates the NF-{kappa}B transcription factor, leading to induction of SOD2. Conversely, the FOXO3a transcription factor is dispensable for mROS-induced SOD2 induction. PKD-mediated MnSOD expression promotes increased survival of cells upon release of mROS, suggesting that mitochondrion-to-nucleus signaling is necessary for efficient detoxification mechanisms and cellular viability.

* Corresponding author. Mailing address: Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RN-237, Boston, MA 02215. Phone: (617) 667-8535. Fax: (617) 667-3616. E-mail: atoker{at}bidmc.harvard.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Mayo Clinic Comprehensive Cancer Center, Department of Cancer Biology, Griffin Cancer Research Building, Rm. 306, 4500 San Pablo Road, Jacksonville, FL 32224.

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