Defects  in  mitochondrial   oxidative  phosphorylation  complexes,
   altered  bioenergetics  and  metabolic  shift  are  often  seen  in
   cancers.  Here we show a role for the  dysfunction  of the electron
   transport chain  component  cytochrome  c  oxidase  (CcO) in cancer
   progression.  We show that genetic silencing of the  CcO complex by
   shRNA expression and loss of CcO  activity  in  multiple cell types
   from the mouse and human  sources  resulted  in  metabolic shift to
   glycolysis,  loss  of   anchorage-dependent   growth  and  acquired
   invasive phenotypes.  Disruption of the CcO complex  caused loss of
   transmembrane potential and induction of Ca2+/Calcineurin- mediated
   retrograde  signaling.   Propagation  of  this  signaling  includes
   activation   of   PI3-kinase,   IGF1R   and   Akt,   Ca2+-sensitive
   transcription factors and also TGF1, MMP16 and periostin, which are
   involved   in   oncogenic   progression.   Whole-genome  expression
   analysis  showed  the  upregulation  of  genes   involved  in  cell
   signaling, extracellular  matrix  interactions, cell morphogenesis,
   cell  motility  and  migration.   The  transcription proles  reveal
   extensive similarity to retrograde  signaling  initiated by partial
   mitochondrial  DNA  depletion,  although  distinct differences  are
   observed in signaling induced by CcO dysfunction.  The possible CcO
   dysfunction as a biomarker for cancer progression  was supported by
   data  showing  that  esophageal  tumors  from  human patients  show
   reduced CcO subunits IVi1 and Vb  in  regions  that were previously
   shown to be the hypoxic core of the tumors.  Our  results show that
   mitochondrial   electron   transport   chain   defect  initiates  a
   retrograde signaling.  These results suggest that  a  defect in the
   CcO complex can potentially induce tumor progression.

   (Oncogene, doi:10.1038/onc.2015.227, 2015)