Bajzikova 2013 Abstract IOC79
|Bajzikova M (2013) Mitochondrially targeted vitamin E succinate and its effects on mitochondrial oxidative phosphorylation system. Mitochondr Physiol Network 18.07.|
Mitochondria are emerging as intriguing targets for anti-cancer agents. We tested the anti-neoplastic activity of a mitochondrially targeted analog of alpha-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis in cancer cells by targeting complex II (CII) of mitochondrial respiratory chain. The parental compound, alpha-tocopheryl succinate (α-TOS), displays anti-cancer properties, and we reasoned to modified VES by tagging the triphenylphosphonium group to its structure to enhance these effects via mitochondrial destabilization. A major mechanism how these compounds cause apoptosis in cancer cells is generation of reactive oxygen species (ROS), most likely the outcome of CII inhibition after α-TOS/MitoVES binding to the proximal UbQ- binding site (Qp) of the SDHC subunit of CII (1,2). The effect of small anti-cancer compounds on mitochondria can involve suppression of their respiration (3). We tested this for α-TOS and MitoVES in malignant mesothelioma (MM) cells, first assessing the effect of the two agents on routine respiration, i.e. total oxygen consumption by whole cells in the cultivation medium in the absence of an uncoupler. MitoVES was much higher efficient in inhibition of respiration than α-TOS, which was relatively inefficient. Interestingly, MitoVES acts as an uncoupler at low concentrations (1–2 μM). We next tested the effect of MitoVES and α-TOS on the contribution of CI and CII to mitochondrial respiration in permeabilized cells. MM cells respire predominantly via CII and reveals a superior effect of MitoVES, which at lower concentrations uncoupled CII-dependent respiration in several of the cell lines, followed by its inhibition. The agent also exerted an effect on CI at higher concentrations. In the next experiments, we tested the effect of the VE analogues on the assembly of mitochondrial (super)complexes. While the assembly of CII, the most sensitive MitoVES target, was not affected, the agent destabilized the higher forms of supercomplexes, referred to as respirasomes. α-TOS was much less efficient. Further, we found that MitoVES suppressed CII and CI activity using the in-gel assay following the separation of the mitochondrial fraction by clear native electrophoresis. These effects on electron transport and oxidative phosphorylation may be explained by the interaction of MitoVES with CII, which results in ROS generation and subsequent effect on mitochondrial (super)complexes, although the exact mechanism is yet to be established. We propose that mitochondrial targeting of VES maximises its anti-cancer efficacy, endowing it with a substantial translational relevance.
• Keywords: cancer cells, VE analogs, CII
• O2k-Network Lab: CZ Prague Neuzil J
Labels: MiParea: Respiration Pathology: Cancer
Organism: Human Tissue;cell: Other cell lines Preparation: Intact cells, Permeabilized cells Enzyme: Complex II;succinate dehydrogenase
Pathway: Other combinations HRR: Oxygraph-2k
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- Dong LF, et al. Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II. J Biol Chem 2011;286(5):3717–28.
- Neuzil J, et al. Classification of mitocans, anti-cancer drugs acting on mitochondria. Mitochondrion 2013;13(3):199–208.
Martina Bajzikova1, Magdalena Vondrusova1, Jiri Neuzil1,2
- Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
- School of Medical Science, Griffith University, Southport, Qld, Australia