Inhibition of mitochondrial permeability transition by deletion of the ANT family and CypD.

The mitochondrial permeability transition pore (MPTP) has resisted molecular identification. The original model of the MPTP that proposed the adenine nucleotide translocator (ANT) as the inner membrane pore-forming component was challenged when mitochondria from Ant1/2 double null mouse liver still had MPTP activity. Because mice express three genes, we reinvestigated whether the ANTs comprise the MPTP. Liver mitochondria from , , and deficient mice were highly refractory to Ca-induced MPTP formation, and when also given cyclosporine A (CsA), the MPTP was completely inhibited. Moreover, liver mitochondria from mice with quadruple deletion of , , , and (cyclophilin D, target of CsA) lacked Ca-induced MPTP formation. Inner-membrane patch clamping in mitochondria from , , and triple null mouse embryonic fibroblasts showed a loss of MPTP activity. Our findings suggest a model for the MPTP consisting of two distinct molecular components: The ANTs and an unknown species requiring CypD.