The voltage-gated potassium channel Kv1.3, the major plasma membrane channel in lymphocytes (Chandy KG et al, 2004 Trends Pharm. Sci., 25, 280), has been located also to the inner mitochondrial membrane in these cells (Szabò et al, 2005, J.Biol. Chem., 280, 12790). Mouse and human cells genetically deficient for Kv1.3 or transfected with siRNA suppressing Kv1.3-expression resisted apoptosis induced by several stimuli, while retransfection of Kv1.3 restored death. Pro-apoptotic Bax directly interacted with and functionally inhibited mitochondrial Kv1.3. Incubation of Kv1.3-positive isolated mitochondria with recombinant Bax or channel inhibiting toxins triggered hyperpolarization, formation of reactive oxygen species, release of cytochrome c and depolarization. In Kv1.3-deficient mitochondria these changes did not occur upon incubation with Bax and the toxins. Mutation of Bax at K128, which corresponds to a conserved lysine in Kv1.3-inhibiting toxins, abrogated its effects on Kv1.3 and mitochondria. Likewise, a single point mutation turned Bcl-xL pro-apoptoptic. To test the function of the mutant Bax in vivo, Bax^-/- Bak^-/- mouse embryonic fibroblasts (DKO MEFs) were transfected with either wild type Bax or Bax(K128E). Staurosporine-induced apoptosis was defective in Bax(K128E)-transfected cells, indicating that Bax mediates apoptosis in lymphocytes at least in part via interaction with mitochondrial Kv1.3.