Mitochondrially Targeted Vitamin E Succinate Modulates Expression of Mitochondrial DNA Transcripts and Mitochondrial Biogenesis

0444249 - BTÚ 2016 RIV US eng J - Článek v odborném periodiku
Truksa, Jaroslav - Dong, L.F. - Rohlena, Jakub - Stursa, J. - Vondrusová, Magdaléna - Goodwin, J. - Nguyen, M. - Klučková, Katarína - Rychtarčíková, Zuzana - Lettlová, Sandra - Spáčilová, Jana - Stapelberg, M. - Zoratti, M. - Neužil, Jiří
Mitochondrially Targeted Vitamin E Succinate Modulates Expression of Mitochondrial DNA Transcripts and Mitochondrial Biogenesis.
Antioxidants & Redox Signaling. Roč. 22, č. 11 (2015), s. 883-900. ISSN 1523-0864. E-ISSN 1557-7716
Grant CEP: GA ČR GAP301/10/1937; GA AV ČR KAN200520703; GA ČR GAP305/12/1708; GA ČR GAP301/12/1851; GA MŠMT(CZ) ED1.1.00/02.0109
Výzkumný záměr: CEZ:AV0Z50520701
Institucionální podpora: RVO:86652036
Klíčová slova: ALPHA-TOCOPHERYL SUCCINATE * ELECTRON-TRANSPORT CHAIN * RESPIRATORY COMPLEX-II
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 7.093, rok: 2015

Aims: To assess the effect of mitochondrially targeted vitamin E (VE) analogs on mitochondrial function and biogenesis. Results: Mitochondrially targeted vitamin E succinate (MitoVES) is an efficient inducer of apoptosis in cancer cells. Here, we show that unlike its untargeted counterpart alpha-tocopheryl succinate, MitoVES suppresses proliferation of cancer cells at sub-apoptotic doses by way of affecting the mitochondrial DNA (mtDNA) transcripts. We found that MitoVES strongly suppresses the level of the displacement loop transcript followed by those of mtDNA genes coding for subunits of mitochondrial complexes. This process is coupled to the inhibition of mitochondrial respiration, dissipation of the mitochondrial membrane potential, and generation of reactive oxygen species. In addition, exposure of cancer cells to MitoVES led to decreased expression of TFAM and diminished mitochondrial biogenesis. The inhibition of mitochondrial transcription was replicated in vivo in a mouse model of HER2(high) breast cancer, where MitoVES lowered the level of mtDNA transcripts in cancer cells but not in normal tissue. Innovation: Our data show that mitochondrially targeted VE analogs represent a novel class of mitocans that not only induce apoptosis at higher concentrations but also block proliferation and suppress normal mitochondrial function and transcription at low, non-apoptogenic doses. Conclusions: Our data indicate a novel, selective anti-cancer activity of compounds that act by targeting mitochondria of cancer cells, inducing significant alterations in mitochondrial function associated with transcription of mtDNA-coded genes. These changes subsequently result in the arrest of cell proliferation
Trvalý link: http://hdl.handle.net/11104/0246797