Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III

Concetta Valentina Tropeano, Jessica Fiori, Valerio Carelli, Leonardo Caporali, Fevzi Daldal, Anna Maria Ghelli, Michela Rugolo

Research output: Contribution to journalArticle

Abstract

A marked stimulation of complex II enzymatic activity was detected in cybrids bearing a homoplasmic MTCYB microdeletion causing disruption of both the activity and the assembly of complex III, but not in cybrids harbouring another MTCYB mutation affecting only the complex III activity. Moreover, complex II stimulation was associated with SDHA subunit tyrosine phosphorylation. Despite the lack of detectable hydrogen peroxide production, up-regulation of the levels of mitochondrial antioxidant defenses revealed a significant redox unbalance. This effect was also supported by the finding that treatment with N-acetylcysteine dampened the complex II stimulation, SDHA subunit tyrosine phosphorylation, and levels of antioxidant enzymes. In the absence of complex III, the cellular amount of succinate, but not fumarate, was markedly increased, indicating that enhanced activity of complex II is hampered due to the blockage of respiratory electron flow. Thus, we propose that complex II phosphorylation and stimulation of its activity represent a molecular mechanism triggered by perturbation of mitochondrial redox homeostasis due to severe dysfunction of respiratory complexes. Depending on the site and nature of the damage, complex II stimulation can either bypass the energetic deficit as an efficient compensatory mechanism, or be ineffectual, leaving cells to rely on glycolysis for survival.

Original languageEnglish
Pages (from-to)182-190
Number of pages9
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1859
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

Keywords

  • Complex III dysfunction
  • Cytochrome b
  • Mitochondria
  • MTCYB gene mutation
  • Respiratory complex II
  • Succinate

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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