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Specific disintegration of complex II succinate:ubiquinone oxidoreductase links pH changes to oxidative stress for

A Lemarie1, L Huc, E Pazarentzos

  • 1Department of Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, Du Cane Road, London, UK.

Cell Death and Differentiation
|August 14, 2010
PubMed

Insights

Intracellular acidification triggers mitochondrial reactive oxygen species (ROS) formation by impairing complex II activity during apoptosis. This pH change dissociates subunits, enabling ROS generation for programmed cell death.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Apoptosis involves reactive oxygen species (ROS) and altered intracellular pH (pH(i)).
  • The precise interplay between pH(i) and ROS in apoptosis remains unclear.
  • Anticancer drugs and cytokines can induce apoptosis.

Purpose of the Study:

  • To elucidate the connection between intracellular acidification and mitochondrial ROS production during apoptosis.
  • To identify the specific molecular mechanisms linking pH changes to ROS generation in programmed cell death.

Main Methods:

  • Investigated the effects of anticancer drugs and cytokines (Fas ligand, TNFα) on pH(i) and mitochondrial ROS.
  • Analyzed the activity of mitochondrial respiratory complex II, specifically succinate:ubiquinone oxidoreductase (SQR) and succinate dehydrogenase (SDH) activities.
  • Examined subunit dissociation within complex II under conditions of intracellular acidification.

Main Results:

  • Intracellular acidification and mitochondrial ROS formation are induced by various apoptosis-triggering agents.
  • Succinate:ubiquinone oxidoreductase (SQR) activity of complex II is specifically impaired during apoptosis.
  • This impairment results from the dissociation of SDHA/SDHB subunits due to decreased pH(i), while SDH activity remains intact.
  • Dissociated complex II acts as an apoptosis mediator, generating superoxides.

Conclusions:

  • Intracellular acidification is a key regulator of mitochondrial ROS production during apoptosis.
  • The pH-dependent dissociation of complex II subunits specifically enables SQR-mediated superoxide generation, promoting cell death.
  • This mechanism highlights a novel role for complex II as an apoptosis effector.

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