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Molecular and Cellular Biology, May 2007, p. 3625-3639, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02295-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Novel Role for Mitochondria: Protein Kinase C{theta}-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death{triangledown}

Marcin Kaminski, 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), PLC{gamma}1 (phospholipase C{gamma}1), and PKC{theta} (protein kinase C{theta}), are crucial for ROS production. PKC{theta} 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{theta}-dependent ROS generation by mitochondrial complex I is essential for AICD.

* Corresponding author. Mailing address: Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49 6221 423765. Fax: 49 6221 411715. E-mail: k.guelow{at}dkfz.de

{triangledown} Published ahead of print on 5 March 2007.

Molecular and Cellular Biology, May 2007, p. 3625-3639, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02295-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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