Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species production, increases hypoxia-inducible factor alpha stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-α

Robert D. Guzy

2007

Scholarcy highlights

  • Mitochondrial complex II is comprised of four subunits that are encoded in the nuclear genome
  • The enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1␣ and/or HIF-2␣, indicating that the mechanism of SdhB-induced tumor formation relies upon reactive oxygen species production and subsequent HIF-␣ activation
  • 3-nitropropionic acid and MMA inhibit the normoxic HIF-1␣ stabilization induced by TTFA, suggesting that the effect of TTFA is specific to its action on complex II and that electrons must enter the SdhA subunit for TTFA to have an effect on HIF-1␣ stabilization
  • The first model suggests that succinate dehydrogenase inhibition arising from mutations in the B, C, or D subunit leads to an increase in ROS production, resulting in oxidative damage to DNA, genomic instability, and tumorigenesis
  • The second model proposes that Sdh mutations lead to an increase in mitochondrial ROS production, but these oxidants act as signal transduction messengers to trigger HIF-1␣ stabilization by inhibiting prolyl hydroxylase, which regulates the stability of the protein through the hydroxylation of two proline residues
  • The ratio of baseline oxidation of roGFP is indicated as 100%; values greater than 100% represent oxidation, whereas values less than 100% represent the reduction of the level of the sensor relative to baseline redox levels. Superoxide production as assessed by DHE fluorescence in wild-type 143B cells treated with AA, TTFA, 3-NPA, or MMA
  • Investigators have examined these mechanisms in diverse model systems, and controversy has arisen with respect to whether or not an ROS increase is involved in the response and why tumorigenesis is associated with mutations in the B, C, and D subunits but not the A subunit
  • Complex II has been classified as a tumor suppressor, but our results suggest that it functions as a protooncogene capable of activating HIF when defects in SdhB, SdhC, or SdhD cause an increase in reactive oxygen species production, leading to the stimulation of HIF-dependent gene expression and cell proliferation

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