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Mitochondrially Targeted Vitamin E Succinate Modulates Expression of Mitochondrial DNA Transcripts and Mitochondrial Biogenesis
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SYSNO ASEP 0444249 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Mitochondrially Targeted Vitamin E Succinate Modulates Expression of Mitochondrial DNA Transcripts and Mitochondrial Biogenesis Author(s) Truksa, Jaroslav (BTO-N) RID, ORCID
Dong, L.F. (AU)
Rohlena, Jakub (BTO-N) RID, ORCID
Stursa, J. (AU)
Vondrusová, Magdaléna (BTO-N) RID
Goodwin, J. (AU)
Nguyen, M. (AU)
Klučková, Katarína (BTO-N) RID
Rychtarčíková, Zuzana (BTO-N)
Lettlová, Sandra (BTO-N)
Spáčilová, Jana (BTO-N)
Stapelberg, M. (AU)
Zoratti, M. (IT)
Neužil, Jiří (BTO-N) RIDSource Title Antioxidants & Redox Signaling. - : Mary Ann Liebert - ISSN 1523-0864
Roč. 22, č. 11 (2015), s. 883-900Number of pages 18 s. Language eng - English Country US - United States Keywords ALPHA-TOCOPHERYL SUCCINATE ; ELECTRON-TRANSPORT CHAIN ; RESPIRATORY COMPLEX-II Subject RIV EB - Genetics ; Molecular Biology R&D Projects GAP301/10/1937 GA ČR - Czech Science Foundation (CSF) KAN200520703 GA AV ČR - Academy of Sciences of the Czech Republic (AV ČR) GAP305/12/1708 GA ČR - Czech Science Foundation (CSF) GAP301/12/1851 GA ČR - Czech Science Foundation (CSF) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support BTO-N - RVO:86652036 CEZ AV0Z50520701 - BTO-N (2007-2013) UT WOS 000351944100001 DOI 10.1089/ars.2013.5594 Annotation 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 Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2016
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