ADP/ATP carrier is required for mitochondrial permeabilization and cytochrome c release in yeast apoptosis

Adenine nucleotide translocator (ANT) is a mitochondrial inner membrane protein involved in the ADP/ATP exchange and is a component of the mitochondrial permeability transition pore (PTP). In mammalian apoptosis, the PTP can mediate mitochondrial outer membrane permeabilization (MOMP), which is suspected to be responsible for the release of apoptogenic factors, including cytochrome c. Although release of cytochrome c in yeast apoptosis has previously been reported, it is not known how it occurs. Herein we used yeast genetics to investigate whether depletion of proteins putatively involved in MOMP and cytochrome c release affects these processes in yeast. While deletion of POR1 (yeast voltage-dependent anion channel) enhances apoptosis triggered by acetic acid, H2O2 and diamide, CPR3 (mitochondrial cyclophilin) deletion had no effect. Absence of ADP/ATP carrier (AAC) proteins, yeast orthologues of ANT, protects cells exposed to acetic acid and diamide but not to H2O2. Expression of a mutated form of Aac2p (op1) exhibiting very low ADP/ ATP translocase activity indicates that AAC's prodeath role does not require translocase activity. Absence of AAC proteins impairs MOMP and release of cytochrome c, which, together with other mitochondrial inner membrane proteins, is degraded. Our findings point to a crucial role of AAC in yeast apoptosis.