Mitochondrial Permeability Transition (PT)

What is the PT?

Under normal conditions, the inner mitochondrial membrane is quasi-impermeable for small molecules, allowing the creation of the electrochemical gradient which is indipensable for mitochondrial function. The opening of PT pores ('megachannels') results in a sudden permeability increase of the inner mitochondrial membrane to solutes < 1500 Da and some proteins, thereby disrupting the deltaPSI and associated mitochondrial functions. In isolated mitochondria, PT is accompanied by colloidosmotic swelling and uncoupling of oxidative phosphorylation, as well as by the loss of low molecular weight matrix molecules such as calcium and glutathione.

How can the PT be detected?

Isolated mitochondria undergoing PT show colloidosmotic, so called Large Amplitude Swelling, what results in a decrease in photometric absorption at 540 nm. Since PT results in the disruption of the mitochondrial transmembrane potential (deltaPSI), PT can be measured indirectly by determining deltaPSI, for example by Patch Clamp Techniques or by using lipophilic fluorochromes (e.g. DiOC6), which act as indicators for an intact deltaPSI.

Molecular composition of the PT pore

The exact molecular composition of the PT pore is not known: it appears that at the inner mitochondrial membrane the adenine nucleotide translocator (ANT) is involved in PT pore formation, in association with several molecules of the outer mitochondrial membrane such as the peripheral benzodiazepine receptor and the voltage-dependent anion channel. ANT ligands such as atractyloside (Atr) and bongkrekic acid (BA) enhance or reduce the probability of PT pore opening, respectively.

Functions of the PT pore

1. The PT pore functions as a Voltage Sensor: the physiological electrochemical proton gradient across the inner mitochondrial membrane results in a transmembrane potential of about - 200 mV. Voltage changes across the mitochondrial membrane influence the probability of pore opening. The PT pore opens at the so called Gating Potential. Pore agonists (e.g. Atractyloside) shift the apparent Gating Potential to more negative values (closer to - 200 mV), thereby favoring pore opening, while pore antagonists (e.g. bongkrekic acid) have the opposite effect and favor its closure.
2. The PT pore is a Thiol Sensor: oxidation of a certain mitochondrial dithiol increases the probability of pore openíng. The redox status of this dithiol is in equilibrium with that of glutathion.
3. The PT is a sensor of Calcium-Ions: Matrix Ca2+ ions increase, whereas external Ca2+ ions decrease the probability of pore opening.

So, speculatively, periodic reversible PT pore opening might allow for the release of calcium from the mitochondrial matrix, thus allowing the maintenance of calcium homeostasis. Alternatively, the PT pore might facilitate the deltaPSI driven import of proteins into the mitochondrial matrix. Massive PT culminates in cell death.


Kroemer et al., 1997, Immunol. Today, 18(1): 44-51