Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Oncogene. 2002 Nov 7;21(51):7839-49. doi: 10.1038/sj.onc.1205983.


We have investigated mechanisms of mitochondrial stress-induced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca(2+)](c), and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFbeta1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X(L) were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFbeta1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondria-to-nucleus signaling pathway operating through increased [Ca(2+)](c) plays an important role in cancer progression and metastasis.

Publication types

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

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Adenosine Triphosphate / biosynthesis
  • Apoptosis
  • Calcium Signaling*
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / toxicity
  • Cathepsin L
  • Cathepsins / genetics
  • Cathepsins / physiology
  • Cysteine Endopeptidases
  • DNA, Mitochondrial / drug effects
  • DNA, Mitochondrial / genetics
  • Electron Transport
  • Electron Transport Complex IV / metabolism
  • Ethidium / toxicity
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Intracellular Membranes / physiology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • MAP Kinase Signaling System
  • Membrane Potentials
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Neoplasm Invasiveness / pathology*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Oligoribonucleotides, Antisense / pharmacology
  • Phenotype
  • Stress, Physiological / pathology*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology
  • Transforming Growth Factor beta1
  • Tumor Cells, Cultured / pathology


  • DNA, Mitochondrial
  • Neoplasm Proteins
  • Oligoribonucleotides, Antisense
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • Cathepsins
  • Cysteine Endopeptidases
  • CTSL protein, human
  • Cathepsin L
  • Ethidium