Reperfusion of ischemic tissue can precipitate cell death. Much of this cell killing is related to the return of physiological pH after the tissue
acidosis of
ischemia. The mitochondrial permeability transition (MPT) is a key mechanism contributing to this pH-dependent
reperfusion injury in hepatocytes, myocytes, and other cell types. When
ATP depletion occurs after the MPT, necrotic cell death ensues. If
ATP levels are maintained, at least in part, the MPT initiates apoptosis caused by mitochondrial swelling and release of
cytochrome c and other proapoptotic factors.
Cyclosporin A and acidotic pH inhibit opening of permeability transition pores and protect cells against oxidative stress and
ischemia/reperfusion injury, whereas Ca(2+), mitochondrial
reactive oxygen species, and pH above 7 promote mitochondrial inner membrane permeabilization. Reperfusion with
nitric oxide (NO) donors also blocks the MPT via a
guanylyl cyclase and
protein kinase G-dependent signaling pathway, which in turn prevents reperfusion-induced cell killing. In isolated mitochondria, a combination of cGMP, cytosolic extract, and
ATP blocks the Ca(2+)-induced MPT, an effect that is reversed by
protein kinase G inhibition. Thus, NO prevents pH-dependent cell killing after
ischemia/reperfusion by a
guanylyl cyclase/cGMP/
protein kinase G signaling cascade that blocks the MPT.