We propose a model for the mechanism of permeability transition (PT) related cytochrome c release. It is likely that the Ca(2+) requirement for the induction of the mitochondrial permeability transition pore (MPTP) opening might be due to the Ca(2+)-dependent interaction between cyclophilin D and ANT. We show here that the modification of adenine nucleotide translocase (ANT), which is one of the components of MPTP, can induce two different types of the cytochrome c release. One is dependent on classical PT, resulting in mitochondrial swelling, and is inhibited by cyclosporin A. The other is PT-independent, without swelling, and is insensitive to cyclosporin A.