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Inhibition of mitochondrial respiration by endogenous nitric oxide: a critical step in Fas signaling

Belén Beltrán1, Marisol Quintero, Eugenia García-Zaragozá

  • 1Centro Nacional de Investigaciones Cardiovasculares, C/Sinesio Delgado, 6 - Pab.5 28029 Madrid, Spain.

Proceedings of the National Academy of Sciences of the United States of America
|June 22, 2002
PubMed

Insights

Activation of Jurkat cells releases nitric oxide (NO), inhibiting respiration and protecting cells. A later phase triggers apoptosis, which NO appears to delay, suggesting a protective role.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Activation of human adult T cell leukemia (Jurkat) cells via anti-Fas antibody (Ab) triggers complex cellular responses.
  • Understanding these responses is crucial for T cell leukemia research and therapeutic development.

Purpose of the Study:

  • To investigate the biphasic response of Jurkat cells to anti-Fas Ab stimulation.
  • To elucidate the roles of nitric oxide (NO), mitochondrial function, and caspase activation in this process.

Main Methods:

  • Jurkat cells were stimulated with anti-Fas Ab in a concentration-dependent manner.
  • Nitric oxide synthase (NOS) and caspase activation inhibitors were used to probe cellular pathways.
  • Mitochondrial membrane potential, respiration, ATP hydrolysis, and free radical production were monitored.

Main Results:

  • An early phase involved NO production, inhibition of cell respiration, mitochondrial hyperpolarization, and transient superoxide release.
  • A second phase, occurring ~2 hours post-stimulation, showed mitochondrial membrane potential collapse, further free radical production, and caspase-8 activation leading to apoptosis.
  • Inhibition of NO synthesis accelerated and enhanced the second phase, indicating NO's protective role in the early phase.

Conclusions:

  • Anti-Fas Ab stimulation induces a biphasic response in Jurkat cells with distinct early (NO-dependent) and late (apoptotic) phases.
  • Early NO production appears to be a protective mechanism against rapid cell death.
  • Further studies are needed to fully understand the implications of these phases for cell survival and death pathways.

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