Members of the Bcl-2 family play key roles as proapoptotic (e.g., Bax) and 
antiapoptotic (e.g., Bcl-x(L)) regulators of programmed cell death. We 
previously identified the mitochondrial potassium channel Kv1.3 as a novel 
target of Bax. Incubating Kv1.3-positive isolated mitochondria with Bax 
triggered apoptotic events, whereas Kv1.3-deficient mitochondria were resistant 
to this stimulus. Mutation of Bax at lysine 128 (BaxK128E) abrogated its effects 
on Kv1.3 and the induction of apoptotic changes in mitochondria. These data 
indicate a toxin-like action of Bax on Kv1.3 to trigger at least some of the 
mitochondrial changes typical for apoptosis. To gain insight into the mechanism 
of Bax-Kv1.3 interaction, we mutated Glu158 of Bcl-x(L) (corresponding to K128 
in Bax) to lysine. This substitution turned Bcl-x(L) proapoptotic. Transfection 
of double knockout (Bax(-/-)/Bak(-/-)) mouse embryonic fibroblasts (DKO MEFs) 
with either wild-type Bax, BaxK128E, or Bcl-x(L)E158K showed that apoptosis 
induced by various stimuli was defective in DKO MEFs and BaxK128E-transfected 
cells, but was recovered upon transfection with Bcl-xLE158K or wild-type Bax. 
Both wild-type Bax and BaxK128E can form similar ion-conducting pores upon 
incorporation into planar lipid bilayers. Our results point to a physiologically 
relevant interaction of Bax with Kv1.3 and further indicate a crucial role of a 
distinct lysine in determining the proapoptotic character of Bcl2-family 
proteins.