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

Authors

Jason Karch, University of Cincinnati
Michael J. Bround, University of Cincinnati
Hadi Khalil, University of Cincinnati
Michelle A. Sargent, University of Cincinnati
Nadina Latchman, CUNY Bernard M Baruch College
Naohiro Terada, University of Florida
Pablo M. Peixoto, CUNY Bernard M Baruch CollegeFollow
Jeffery D. Molkentin, University of Cincinnati

Document Type

Article

Publication Date

8-28-2019

Abstract

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.

Comments

This article was originally published in Science Advances, available at https://doi.org/10.1126/sciadv.aaw4597.

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