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

• Published in: Cell death and differentiation Vol. 18; no. 2; pp. 338 - 349
• Main Authors: Lemarie, A, Huc, L, Pazarentzos, E, Mahul-Mellier, A-L, Grimm, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2011; Nature Publishing Group
• Subjects: 631/45/127; 631/45/607/1167; 631/80/642/333; 631/80/82/23; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Cycle Analysis; Cell death; Cytokines; Dehydrogenases; Drugs; Electron Transport Complex II - antagonists & inhibitors; Electron Transport Complex II - metabolism; HeLa Cells; Humans; Hydrogen-Ion Concentration; Life Sciences; Ligands; Mitochondria - metabolism; Original Paper; Oxidative Stress; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Stem Cells; Succinate Dehydrogenase - genetics; Succinate Dehydrogenase - metabolism; Thenoyltrifluoroacetone - pharmacology; Toxicology; Tumor necrosis factor-TNF; United Kingdom > UK; apoptosis; mitochondria; respiratory chain; complex II; ROS; reactive oxygen species
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.93

The formation of reactive oxygen species (ROS) and the change of the intracellular pH (pH
i
) are common phenomena during apoptosis. How they are interconnected, however, is poorly understood. Here we show that numerous anticancer drugs and cytokines such as Fas ligand and tumour necrosis factor
α
provoke intracellular acidification and cause the formation of mitochondrial ROS. In parallel, we found that the succinate:ubiquinone oxidoreductase (SQR) activity of the mitochondrial respiratory complex II is specifically impaired without affecting the second enzymatic activity of this complex as a succinate dehydrogenase (SDH). Only in this configuration is complex II an apoptosis mediator and generates superoxides for cell death. This is achieved by the pH
i
decline that leads to the specific dissociation of the SDHA/SDHB subunits, which encompass the SDH activity, from the membrane-bound components of complex II that are required for the SQR activity.