Identifying the components of the elusive mitochondrial permeability transition pore

The mitochondrial permeability transition pore (MPTP) describes an inducible activity that regulates solute exchange between mitochondrial matrix contents and the surrounding cytoplasm, which acutely leads to loss of mitochondrial inner membrane potential but eventually organelle swelling and rupture. Mitochondrial rupture due to prolonged MPTP engagement, which is often the result of ischemic cellular injury due to elevated intracellular Ca2+ levels and reactive oxygen species, underlies regulated necrotic cell death. An understanding of the molecular constituents that generate the MPTP, as well as the other proteins that can affect it, is of profound disease relevance. However, the molecular identity of the MPTP has been the subject of a protracted scientific debate for nearly three decades. In PNAS, Alavian et al. make a strong case that the c-subunit of the F1FO ATP synthase forms the inner mitochondrial membrane pore of the MPTP (1).