TY - JOUR
T1 - Nitric oxide
T2 - A signaling molecule against mitochondrial permeability transition- and pH-dependent cell death after reperfusion
AU - Kim, Jae Sung
AU - Ohshima, Shigetoshi
AU - Pediaditakis, Peter
AU - Lemasters, John J.
N1 - Funding Information:
This work was supported, in part, by Grants DK59340, AG07218, DK37034, and DK37034 from the National Institutes of Health. Imaging facilities were supported, in part, by Center Grants DK34987 and AA11605.
PY - 2004/12/15
Y1 - 2004/12/15
N2 - 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.
AB - 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.
KW - Free radicals
KW - Ischemia
KW - Mitochondrial permeability transition
KW - Nitric oxide
KW - Reperfusion
UR - http://www.scopus.com/inward/record.url?scp=8544250579&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2004.09.014
DO - 10.1016/j.freeradbiomed.2004.09.014
M3 - Review article
C2 - 15544914
AN - SCOPUS:8544250579
SN - 0891-5849
VL - 37
SP - 1943
EP - 1950
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 12
ER -