Cookies help us deliver our services. By using our services, you agree to our use of cookies. More information

Moreno-Sanchez 2013 FEBS J

From Bioblast
Publications in the MiPMap
Moreno-Sánchez R, Hernández-Esquivel L, Rivero-Segura NA, Marín-Hernández A, Neuzil J, Ralph SJ, Rodríguez-Enríquez S (2013) Reactive oxygen species are generated by the respiratory Complex II - evidence for lack of contribution of the reverse electron flow in Complex I. FEBS J 280:927-38.

» PMID 23206332; PDF

Moreno-Sanchez R, Hernandez-Esquivel L, Rivero-Segura NA, Marin-Hernandez A, Neuzil J, Ralph SJ, Rodriguez-Enriquez S (2013) FEBS J

Abstract: Succinate-driven oxidation via Complex II (CII) may have a significant contribution towards the high rates of production of reactive oxygen species (ROS) by mitochondria. Here, we show that the CII Q site inhibitor thenoyltrifluoroacetone (TTFA) blocks succinate + rotenone-driven ROS production, whereas the Complex III (CIII) Qo inhibitor stigmatellin has no effect, indicating that CII, not CIII, is the ROS-producing site. The complex I (CI) inhibitor rotenone partially reduces the ROS production driven by high succinate levels (5 mM), which is commonly interpreted as being due to inhibition of a reverse electron flow from CII to CI. However, experimental evidence presented here contradicts the model of reverse electron flow. First, ROS levels produced using succinate + rotenone were significantly higher than those produced using glutamate + malate + rotenone. Second, in tumor mitochondria, succinate-driven ROS production was significantly increased (not decreased) by rotenone. Third, in liver mitochondria, rotenone had no effects on succinate-driven ROS production. Fourth, using isolated heart or hepatoma (AS-30D) mitochondria, the CII Qp anti-cancer drug mitochondrially targeted vitamin E succinate (MitoVES) induced elevated ROS production in the presence of low levels of succinate (0.5 mM), but rotenone had no effect. Using sub-mitochondrial particles, the Cu-based anti-cancer drug Casiopeina II-gly enhanced succinate-driven ROS production. Thus, the present results are inconsistent with and question the interpretation of reverse electron flow from CII to CI and the rotenone effect on ROS production supported by succinate oxidation. Instead, a thermodynamically more favorable explanation is that, in the absence of CIII or Complex IV (CIV) inhibitors (which, when added, facilitate reverse electron flow by inducing accumulation of ubiquinol, the CI product), the CII redox centers are the major source of succinate-driven ROS production. Keywords: Anti-cancer drugs; Mitochondria; Respiratory complex II; Reverse electron flow; ROS

O2k-Network Lab: CZ Prague Neuzil J

Labels: Pathology: Cancer  Stress:Oxidative stress;RONS 

Tissue;cell: Heart, Liver  Preparation: Isolated mitochondria, SMP  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III 

Pathway: N, S