Modulation of the mitochondrial permeability transition by cyclophilin D: moving closer to F(0)-F(1) ATP synthase?
- PMID: 21586346
- DOI: 10.1016/j.mito.2011.04.007
Modulation of the mitochondrial permeability transition by cyclophilin D: moving closer to F(0)-F(1) ATP synthase?
Abstract
Cyclophilin D was recently shown to mask an inhibitory site of the mitochondrial permeability transition pore (PTP) for phosphate, and to constitutively bind F(0)-F(1) ATP synthase resulting in the slowing of ATP synthesis and hydrolysis rates, thus regulating matrix adenine nucleotide levels. Here we review the striking similarities of the factors affecting the threshold for PTP induction, to those affecting binding of phosphate to formerly proposed sides on F(1)-ATPase affecting ATP hydrolytic activity, including critical arginine residues, matrix pH, [Mg(2+)], adenine nucleotides and proton motive force. Based on these similarities, we scrutinize the hypothesis that in depolarized mitochondria exhibiting reversal of F(0)-F(1) ATP synthase operation, the genetic ablation of cyclophilin D or its inhibition by cyclosporin A results in accelerated proton pumping by ATP hydrolysis, opposing a further decrease in membrane potential and promoting high matrix phosphate levels, both negatively affecting the probability of PTP opening.
Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
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