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Mol. Cell. Biol. doi:10.1128/MCB.02295-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Novel Role for Mitochondria: Protein Kinase C theta Dependent Oxidative Signalling Organelles in Activation Induced T cell Death

Marcin Kamiski, Michael Kießling, Dorothee Süss, Peter H. Krammer, and Karsten Gülow^*

Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany

^* To whom correspondence should be addressed. Email: k.guelow{at}dkfz.de.

	Abstract

Reactive oxygen species (ROS) play a key role in regulation of Activation Induced T cell Death (AICD) by induction of CD95L expression. However, the molecular source and the signalling steps necessary for ROS production are largely unknown. Here we show that the proximal T cell receptor (TCR) signalling machinery including the zeta chain associated protein kinase 70 (ZAP70), the linker of activated T cells (LAT), the SH2-domain-containing leukocyte protein of 76kd (SLP76), phospholipase C1 (PLC1) and protein kinase C theta (PKC) are crucial for ROS production. PKC is translocated to the mitochondria. By using cells depleted in mitochondrial DNA we identified the mitochondria as source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by siRNA-mediated knockdown of the chaperon NDUFAF1 resulted in a block of ROS production. Complex I derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase (MnSOD). This signal is essential for CD95L expression as inhibition of complex I assembly by NDUFAF1 specific siRNA prevents AICD. Similar results were obtained when metformin, an anti-diabetic drug and mild complex I inhibitor was used. Thus, we demonstrate, for the first time, that PKC-dependent ROS generation by mitochondrial complex I is essential for AICD.

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