The mitochondrial permeability transition pore: a mystery solved?

Abstract

The permeability transition (PT) denotes an increase of the mitochondrial inner membrane permeability to solutes with molecular masses up to about 1500 Da. It is presumed to be mediated by opening of a channel, the permeability transition pore (PTP), whose molecular nature remains a mystery. Here I briefly review the history of the PTP, discuss existing models, and present our new results indicating that reconstituted dimers of the FOF1 ATP synthase form a channel with properties identical to those of the mitochondrial megachannel (MMC), the electrophysiological equivalent of the PTP. Open questions remain, but there is now promise that the PTP can be studied by genetic methods to solve the large number of outstanding problems.

Keywords: FOF1 ATP synthase; calcium; mitochondria; permeability transition.

Figure 1

Schematic representation of F_OF₁ ATP synthase dimers. F₁ (dark blue), F_O (green and light blue), and stalk subunits (red) are illustrated based on recent structural studies (Strauss et al., ; Baker et al., ; Davies et al., 2012).

Figure 2

Hypothetical transition of F_OF₁ ATP synthase dimers to form the PTP. ATP synthase dimers (A) can undergo PTP formation when Ca²⁺ rather than Mg²⁺ is bound, possibly at the catalytic sites, in a reversible process favored by thiol oxidation (C). Binding of CyPD, which is favored by Pi (B) would increase the accessibility of the metal binding sites, allowing PTP formation at lower Ca²⁺ concentrations (as depicted here by a smaller face type) (D). Adenine nucleotides counteract PTP formation in synergy with Mg²⁺. Red arrows denote the hypothetical pathway for solute diffusion between two F_O subunits.