Physiological roles of the mitochondrial permeability transition pore

Abstract

Neurons experience high metabolic demand during such processes as synaptic vesicle recycling, membrane potential maintenance and Ca²⁺ exchange/extrusion. The energy needs of these events are met in large part by mitochondrial production of ATP through the process of oxidative phosphorylation. The job of ATP production by the mitochondria is performed by the F₁F_O ATP synthase, a multi-protein enzyme that contains a membrane-inserted portion, an extra-membranous enzymatic portion and an extensive regulatory complex. Although required for ATP production by mitochondria, recent findings have confirmed that the membrane-confined portion of the c-subunit of the ATP synthase also houses a large conductance uncoupling channel, the mitochondrial permeability transition pore (mPTP), the persistent opening of which produces osmotic dysregulation of the inner mitochondrial membrane, uncoupling of oxidative phosphorylation and cell death. Recent advances in understanding the molecular components of mPTP and its regulatory mechanisms have determined that decreased uncoupling occurs in states of enhanced mitochondrial efficiency; relative closure of mPTP therefore contributes to cellular functions as diverse as cardiac development and synaptic efficacy.

Keywords: ATP synthase; Mitochondria; Permeability transition pore; Synaptic plasticity; Synaptic transmission.

Fig. 1

Mitochondrial Ca²⁺ buffering contributes to post-tetanic potentiation of neurotransmitter release. Images left to right show how Ca²⁺ uptake by and re-release from mitochondria enhance synaptic vesicle fusion and thereby increase neurotransmission

Fig. 2

Mitochondrial Ca²⁺ is necessary for short term synaptic plasticity. Left panel demonstrates that mitochondrial Ca²⁺ contributes to the Ca²⁺ remaining in the synapse for about 1 min after a tetanus. After a tetanus, postsynaptic potentials initiated by neurotransmitter release are potentiated briefly. The right panel demonstrates that residual Ca²⁺ is necessary for these short term increases in neurotransmission. Both residual Ca²⁺ and posttetanic potentiation are dependent on mitochondrial Ca²⁺ release and are prevented by elimination of mitochondrial Ca²⁺ handling

Fig. 3

Mitochondrial channel activity is necessary for short term plasticity. a Mitochondrial membrane recording obtained during and after brief high frequency stimulation (tetanus) given to the presynaptic nerve. Stimulation leads to delayed increases in mitochondrial membrane conductance that outlast the tetanus for up to 1 min. b Mitochondrial membrane recording obtained during and after brief high frequency stimulation (tetanus) given to the presynaptic nerve in the presence of the mitochondrial protonophore FCCP. FCCP prevents the change in mitochondrial membrane conductance after a tetanus. c FCCP prevents short term posttetanic potentiation of neurotransmitter release

Fig. 4

Recovery of the readily releasable pool of neurotransmitter is regulated by Bcl-x_L. a Change in postsynaptic potential (PSP) amplitude over time in recordings from synapses undergoing repeated tetani. During the tetanus, depression of PSP amplitude occurs followed by rapid recovery in PSP amplitude after the tetanus. b, c Recovery time of PSP amplitude is prolonged by the Bcl-x_L inhibitor ABT-737, preventing recovery of the readily releasable pool of synaptic vesicles. d Diagram demonstrating three different synaptic vesicle pools. The readily releasable pool is defined as those vesicles that are docked at the presynaptic membrane and ready for release. Recovery of docked vesicles takes time and is dependent on Ca²⁺ and the Ca²⁺ binding protein calmodulin. e (left panel) During frequent stimulation at 2 Hz, there is no time for recovery of the readily releasable pool. Bcl-x_L injection into the presynaptic terminal does not influence recovery to the recycling pool that is releasing neurotransmitter at this frequency. (right panel) Bcl-x_L enhances the rate of recovery to the readily releasable pool that most slowly recovers after a tetanus. Therefore Bcl-x_L enhances the rate of recovery of this slowly recovering vesicle pool during stimulation at 0.03 Hz

Fig. 5

The c-subunit of the ATP synthase forms the mPTP. a The c-subunit ring expands and the F₁ lifts away from the mouth of the pore when Ca²⁺ interacts with F₁. b Bcl-x_L or ATP/ADP binding to the β subunit or CsA interacting with CypD on OSCP prevent F₁ removal from the mouth of the mPT pore. These mPTP inhibitors also decrease c-subunit ring diameter and channel conductance. The relative closure of the leak channel within the c-subunit ring provides enhanced coupling to the inner membrane, improving the efficiency of ATP production by the ATP synthase