Metaxin is required for tumor necrosis factor-induced cell death

We used retrovirus insertion-mediated random mutagenesis and tumor necrosis factor (TNF) selection to generate TNF-resistant lines from L929 cells. Th e metaxin gene, which encodes a protein located on the outer membrane of mi tochondria, was identified to be the gene disrupted in one of the resistant lines. The requirement of metaxin in TNF-induced cell death of L929 was co nfirmed by the restoration of TNF sensitivity after ectopic reconstitution of metaxin expression. Analysis of the cell death induced by other stimuli revealed that metaxin deficiency-mediated death resistance was selective to certain stimuli. Studies using deletion mutants of metaxin showed that mit ochondrial association of metaxin is required for the function of metaxin. Over-expression of truncated metaxin lacking the mitochondria anchoring seq uence mimicked metaxin deficiency in wild-type cells. Interfering with meta xin prevented TNF-induced necrotic cell death in L929 cells and apoptosis i n MCF-7 cells. Our work has thus defined a novel component in the death pat hway used by TNF and some other death stimuli.