Molecular Identity of the Mitochondrial Permeability Transition Pore

Upon a cell death stimulus, cardiac mitochondria undergo a rapid increase in inner membrane permeability, the so-called mitochondrial permeability transition (MPT). This results in the inhibition of ATP synthesis, swelling, and ultimately mitochondrial rupture. The MPT pore, a non-specific channel thought to span both mitochondrial membranes, mediates these catastrophic increases in mitochondrial permeability. Based upon biochemical and pharmacological studies, the pore was proposed to consist of the voltage-dependent anion channel (VDAC) in the outer membrane, the adenine nucleotide translocase (ANT) in the inner membrane, plus CypD in the matrix. However, mice lacking ANT still exhibit a classical MPT phenomenon and respond normally to cell death stimuli. Therefore, the exact composition of the pore remains uncertain. To this end, we have studied mice lacking VDAC or CypD. Mitochondria from CypD-null mice are resistant to Ca2+-induced permeability transition. Moreover, CypD-deficient cells are protected against Ca2+- and oxidative stress-induced death, and CypD-null mice are less sensitive to myocardial ischemia/reperfusion injury and cardiac Ca2+ overload. In comparison, permeability transition and cell death progress normally in cells lacking all 3 VDAC isoforms. Therefore