Gene

Programmed cell death

Cell biology

Transition (genetics)

Adenine nucleotide translocator

Mitochondrial permeability transition pore

Ecology

Inner mitochondrial membrane

Biology

Permeability (electromagnetism)

Endocrinology

Apoptosis

Biochemistry

Dopamine

Mitochondrial membrane transport protein

Computational biology

Dopaminergic

Genetics

Bacterial outer membrane

Voltage-dependent anion channel

Membrane

Nucleotide

Adenine nucleotide

Escherichia coli

Mitochondrion

MPTP

Chemistry

Science Advances

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 Ant genes, we reinvestigated whether the ANTs comprise the MPTP. Liver mitochondria from Ant1, Ant2, and Ant4 deficient mice were highly refractory to Ca2+-induced MPTP formation, and when also given cyclosporine A (CsA), the MPTP was completely inhibited. Moreover, liver mitochondria from mice with quadruple deletion of Ant1, Ant2, Ant4, and Ppif (cyclophilin D, target of CsA) lacked Ca2+-induced MPTP formation. Inner-membrane patch clamping in mitochondria from Ant1, Ant2, and Ant4 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.

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