The mitochondrial permeability transition pore (mPTP) is a large, non-selective channel that opens in the inner mitochondrial membrane when the matrix becomes overloaded with calcium, when reactive oxygen species accumulate, and when the membrane potential collapses. During ischemia, the acidic intracellular pH keeps the pore closed even as calcium rises. At reperfusion, the rapid washout of protons restores a neutral pH while calcium and reactive oxygen species are still high, and the pore opens. Once open, it allows solutes up to about 1.5 kDa to cross the inner membrane, dissipating the proton gradient that drives ATP synthesis. The mitochondrion cannot recover its membrane potential, ATP production stops permanently, and the organelle releases cytochrome c and other pro-apoptotic factors. This is the point at which the cell is committed to death. Reperfusion also generates a burst of reactive oxygen species through several routes: the electron transport chain, where electrons that accumulated during ischemia are passed to residual oxygen and form superoxide; xanthine oxidase, which converts hypoxanthine to xanthine and uric acid; and activated neutrophils that arrive with restored flow. These reactive oxygen species oxidize membrane lipids, damage proteins, and further sensitize the mPTP. The clinical consequence is that reperfusion is not purely restorative. It salvages myocardium that was still reversibly injured, but it can also kill cells that would have survived a slower, less abrupt return of flow, a phenomenon called reperfusion injury. The mPTP is the target of cyclosporine and other inhibitors studied for this reason.
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The mitochondrial permeability transition pore and reperfusion injury
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Watch the inner mitochondrial membrane as the animation moves through ischemia and into reperfusion. During ischemia, calcium is already rising inside the matrix, but the acidic pH keeps the pore shut, so the mitochondrion is stressed yet still capable of making ATP. The moment flow returns, protons are washed out, pH normalizes, and with calcium and reactive oxygen species still elevated the pore springs open. Solutes pour across the inner membrane, the proton gradient that drives ATP synthesis collapses, and the mitochondrion can never rebuild its membrane potential. That is the commitment point. The same reperfusion that saves reversibly injured cells can therefore kill cells that were on the edge, which is why the injury is not simply the sum of the ischemic minutes.
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