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First published online 3 March 2009
doi: 10.1242/jcs.041061

Journal of Cell Science 122, 919-928 (2009)
Published by The Company of Biologists 2009
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Research Article

Mitochondrial diacylglycerol initiates protein-kinase-D1-mediated ROS signaling

Catherine F. Cowell1, Heike Döppler1, Irene K. Yan1, Angelika Hausser2, Yoshio Umezawa3 and Peter Storz1,*

1 Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Building, Room 306, 4500 San Pablo Road, Jacksonville, FL 32224, USA
2 Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany
3 Department of Chemistry, School of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

* Author for correspondence (e-mail: storz.peter{at}mayo.edu)

Accepted 21 November 2008

Increases in reactive oxygen species (ROS) have been implicated in age-related diseases, including cancer. The serine/threonine kinase protein kinase D1 (PKD1) is a stress-responsive kinase and sensor for reactive oxygen species, which can initiate cell survival through NF-{kappa}B signaling. We have previously shown that in response to ROS, PKD1 is activated at the mitochondria. However, the initial signaling events leading to localization of PKD1 to the mitochondria are unknown. Here, we show that formation of mitochondrial diacylglycerol (DAG) and its binding to PKD1 is the means by which PKD1 is localized to the mitochondria in response to ROS. Interestingly, DAG to which PKD1 is recruited in this pathway is formed downstream of phospholipase D1 (PLD1) and a lipase-inactive PLD1 or inhibition of PLD1 by pharmacological inhibitors blocked PKD1 activation under oxidative stress. To date it has been viewed that monosaturated and saturated DAG formed via PLD1 have no signaling function. However, our data describe a role for PLD1-induced DAG as a competent second messenger at the mitochondria that relays ROS to PKD1-mediated mitochondria-to-nucleus signaling.

Key words: Mitochondria, DAG, oxidative stress, ROS, PLD, PKD


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