Figure 4. Mitochondrial death channels.

Proteins associated with the MPTP include VDAC, ANT and CypD. The IMAC and phosphate ion channels have also been implicated. Structural elements of MOMP has not been defined structurally, but channel activity is regulated by interactions of Bax, Bak and tBid; some studies implicate VDAC as a component of MOMP while others suggest that Bax not only regulates MOMP, but may also be a structural component. Mitochondrial permeability transition and MOMP are induced by calcium and oxidative stress and Bcl-2 proteins may regulate both. Some reports suggest that VDAC and ANT bridge the IM and OM by interacting at contact points. Other reports suggest that neither ANT nor VDAC are required for MPTP function but both ANT and CypD regulate MPTP opening. The MPTP opens under conditions of ischemia–reperfusion when matrix calcium and reactive oxygen levels increase. Cytochrome c release from the intermembrane space and ICS triggers apoptosis by activating the apoptosome, followed by caspase and DNAse activation. Approximately 15% of total cytochrome c is in the IMS and the rest is in the ICS; membrane fission and fusion events regulated in part by Bax and tBid are required for efficient release of cytochrome c. Low matrix pH inhibits the opening of the MPTP when ΔTM is dissipated but a low pH induces MPTP opening in energized mitochondria.

ΔTM: Membrane potential; ANT: Adenine nucleotide translocase; BDR: Benzodiazepine receptor; CypD: Cyclophilin D; ICS: Intercristal space; IM: Inner membrane; IMAC: Inner membrane anion channel; IMS: Inter-membrane space; MAC: Membrane anion channel; mCU: Mitochondrial uniporter; MOMP: Mitochondrial outer membrane permeability; MPTP: Mitochondrial permeability transition pore; OM: Outer membrane; PiC: Phosphate ion channel; ROS: Reactive oxygen species; VDAC: Voltage-dependent anion channel.