THE 55-KDA TUMOR-NECROSIS-FACTOR RECEPTOR INDUCES CLUSTERING OF MITOCHONDRIA THROUGH ITS MEMBRANE-PROXIMAL REGION

The cytokine tumor necrosis factor (TNF) activates diverse signaling m olecules resulting in gene expression, differentiation, and/or cell de ath. Here we report a novel feature induced by TNF, namely translocati on of mitochondria from a dispersed distribution to a perinuclear clus ter. Mitochondrial translocation correlated with sensitivity to the ce ll death-inducing activity of TNF and was mediated by the 55-kDa TNF r eceptor (TNF-R55), but not by Fas, indicating that the signaling pathw ay requires a TNF-RBS-specific but death domain-independent signal. In deed, using L929 cells that express mutant TNF-R55, we showed that the membrane-proximal region of TNF-R55 was essential for signaling to mi tochondrial translocation. In the absence of translocation, the cell d eath response was markedly delayed, pointing to a cooperative effect o n cell death, Translocation of mitochondria, although dependent on the microtubules, was not imposed by the latter and was equally induced b y TNF-independent immunoinhibition of the motor protein kinesin, Addit ionally, immunoinhibition with antibody directed against the tail doma in of kinesin synergized with TNF-induced cell death. Based on this fu nctional mimicry, we propose that a TNF-R55 membrane-proximal region-d ependent signal impedes mitochondria-associated kinesin, resulting in cooperation with the TNF-R55 death domain-induced cytotoxic response a nd causing the observed clustering of mitochondria.