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Mitochondria-encoded Cytochrome B (CYTB) gene mutations were reported in different cancers, but the effect of these mutations on cellular metabolism and growth is unknown. In a murine xenograft and human model of bladder cancer, we show the functional effect of overexpression of a 21-bp deletion mutation (mt) of CYTB. Overexpression of mtCYTB generated increased reactive oxygen species (ROS) accompanied by increased oxygen consumption and lactate production. MtCYTB overexpression induced significant tumor growth in vitro and in vivo by triggering rapid cell cycle progression through up-regulation of the nuclear factor-κB2 signaling pathway. Tumor-generated ROS induced in vitro lysis of normal splenocytes. Thus, we present physiologic and functional evidence for the role of a bonafide mitochondrial gene mutation in cancer. [Cancer Res 2008;68(3):700–06]