Nitric oxide: A signaling molecule against mitochondrial permeability transition- and pH-dependent cell death after reperfusion

Jae Sung Kim, Shigetoshi Ohshima, Peter Pediaditakis, John J. Lemasters

Research output: Contribution to journalReview articlepeer-review

66 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1943-1950
Number of pages8
JournalFree Radical Biology and Medicine
Volume37
Issue number12
DOIs
StatePublished - Dec 15 2004
Externally publishedYes

Keywords

  • Free radicals
  • Ischemia
  • Mitochondrial permeability transition
  • Nitric oxide
  • Reperfusion

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