Mechanobiology June 26th - June 2nd 2016

Mechanobiology: June 26th  - June 2nd 2016


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-κB 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.


  • We thank Tim Eiseler for help with the FRET analysis. We also thank Mordechai Liscovitch (Weizmann Institute, Israel) for a PLD1 expression plasmid, Michael A. Frohman (SUNY Stony Brook, NY) for a mitoPLD expression plasmid and Alex Toker (Harvard Medical School, MA) for the PLCγ antibody. This work was in part sponsored by funds from the Mayo Foundation and the Mayo Comprehensive Cancer Center, as well as by a R21 from the NCI (CA135102) to P.S. and a DFG grant (DFG HA3557/2-1) to A.H. The authors declare that they have no competing financial interests. Deposited in PMC for release after 12 months.

  • Supplementary material available online at

  • Accepted November 21, 2008.
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