Figure 2. MPTP-dependent necrotic pathway.

When a cell receives a stress that leads to increased levels of intracellular calcium, the mitochondrial calcium uniporter (MCU) takes up the calcium into the matrix of the mitochondria where it can trigger MPTP opening through CypD. The MPTP is thought to be composed of the F₁F₀ ATP synthase regulated by ANT and the mitochondrial phosphate carrier (PiC). Upon prolonged opening of the MPTP there is an osmotic alteration and mitochondrial swelling and dysfunction occurs with loss of ATP production and ROS generation. MPTP-dependent mitochondrial dysfunction requires the presence of Bax or Bak on the outer mitochondrial membrane. Therefore, proteins that affect the content of Bax/Bak on the outer mitochondrial membrane, such as the pro-survival the Bcl-2 family members, can secondarily affect MPTP-dependent mitochondrial dysfunction. Abbreviations: IMM, inner mitochondrial membrane; IMS, intra-mitochondrial membrane space; OMM, outer mitochondrial membrane; ROS, reactive oxygen species; ANT, adenine nucleotide translocator.