Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis

Biol Chem. Mar-Apr 2002;383(3-4):411-23. doi: 10.1515/BC.2002.045.

Abstract

Nitric oxide, generated by endogenous nitric oxide synthases or nitric oxide donors, can promote or prevent apoptosis induced by diverse pro-apoptotic stimuli in cell culture models. Both mitochondrial-dependent and -independent apoptotic signaling pathways mediate this dichotomous cellular response to nitric oxide. The molecular mechanisms behind these effects are complex and involve a number of nitrogen oxide-related species that are more reactive than nitric oxide itself. The local cellular environment plays a dynamic role in determining the nature and concentration of these species. Important components of the microenvironment include: the cellular redox state, glutathione, transition metals and the presence of other oxygen- and nitrogen-centered radicals. In particular, redox-sensitive nitrosating species are favorably generated under physiological conditions and capable of modifying multiple cell signaling pathways through reversible S-nitrosation reactions. Cytochrome c release from mitochondria is an important mechanism for the activation of caspase-3 and the initiation of cell death in response to 'intrinsic' pro-apoptotic stimuli, including oxidative and nitrosative stress. In turn, caspases and mitogen associated protein kinases may modulate cytochrome c release through their effects on the Bcl-2 family of proteins. This review will focus on (i) the importance of the cellular environment in determining the fate of nitric oxide and (ii) the ability of S-nitrosation to regulate mitochondrial-dependent apoptosis at the level of mitochondrial bioenergetics, cytochrome c release, caspases, mitogen associated protein kinases, and the Bcl-2 family of proteins.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Caspase 3
  • Caspases / metabolism
  • Cytochrome c Group / metabolism
  • Humans
  • Mitochondria / physiology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide / physiology*
  • Signal Transduction / physiology*

Substances

  • Cytochrome c Group
  • Nitric Oxide
  • Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases