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Novel Role for Mitochondria: Protein Kinase C-Dependent Oxidative Signaling 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

Received 8 December 2006/ Returned for modification 31 January 2007/ Accepted 26 February 2007

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 signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), LAT (linker of activated T cells), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), PLC1 (phospholipase C1), and PKC (protein kinase C), are crucial for ROS production. PKC is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA)-mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. 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 antidiabetic 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.

Published ahead of print on 5 March 2007.

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