title: Mitochondrially targeted vitamin E succinate modulates expression of mitochondrial DNA transcripts and mitochondrial biogenesis.
abstract: OBJECTIVE
  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 α-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.
  
  
  METHODS
  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.
authors.affiliation: 1 Molecular Therapy Group, Institute of Biotechnology , Academy of Sciences of the Czech Republic, Prague, Czech Republic .
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Truksa
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.forename: Jakub
authors.initials: J
authors.lastname: Rohlena
authors.forename: Jan
authors.initials: J
authors.lastname: Stursa
authors.forename: Magdalena
authors.initials: M
authors.lastname: Vondrusova
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.forename: Maria
authors.initials: M
authors.lastname: Nguyen
authors.forename: Katarina
authors.initials: K
authors.lastname: Kluckova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Rychtarcikova
authors.forename: Sandra
authors.initials: S
authors.lastname: Lettlova
authors.forename: Jana
authors.initials: J
authors.lastname: Spacilova
authors.forename: Michael
authors.initials: M
authors.lastname: Stapelberg
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009369:Neoplasms / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D024502:alpha-Tocopherol; C508053:ERBB2 protein, human