Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis

Gene. 2005 Jul 18;354:132-9. doi: 10.1016/j.gene.2005.03.028.


Depletion of mitochondrial DNA (mtDNA) or treatment with mitochondrial poison CCCP initiates mitochondrial stress signaling, which operates through altered Ca2+ homeostasis. In C2C12 rhabdomyoblasts and A549 human lung carcinoma cells mitochondrial stress signaling activates calcineurin and a number of Ca2+ responsive factors including ATF, NFAT, CEBP/delta and CREB. Additionally, PKC and MAP kinase are also activated. A number of nuclear gene targets including those involved in Ca2+ storage/release (RyR1, calreticulin, calsequestrin), glucose metabolism (hexokinase, pyruvate kinase, Glut4), oncogenesis (TGFbeta1, cathepsin L, IGFR1, melanoma antigen) and apoptosis (Bcl-2, Bid, Bad, p53) are upregulated. Mitochondrial stress in both C2C12 myoblasts and A549 cells induced morphological changes and invasive phenotypes. These cells also showed markedly increased resistance to etoposide-induced apoptosis that is a hallmark of highly invasive tumors. Our results describe a new mechanism of altered nuclear gene expression and phenotypic changes triggered by mitochondrial dysfunction and mtDNA damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blotting, Northern
  • Blotting, Western
  • Calcium / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / genetics*
  • DNA, Mitochondrial / genetics*
  • Drug Resistance / genetics
  • Etoposide / pharmacology
  • Gene Expression / genetics
  • Humans
  • In Situ Nick-End Labeling
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Mutation
  • NF-kappa B / metabolism
  • NFATC Transcription Factors / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / genetics*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism


  • DNA, Mitochondrial
  • NF-kappa B
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • bcl-2-Associated X Protein
  • Etoposide
  • Adenosine Triphosphate
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Calcium