Mitochondrial levels determine variability in cell death by modulating apoptotic gene expression

Nat Commun. 2018 Jan 26;9(1):389. doi: 10.1038/s41467-017-02787-4.


Fractional killing is the main cause of tumour resistance to chemotherapy. This phenomenon is observed even in genetically identical cancer cells in homogeneous microenvironments. To understand this variable resistance, here we investigate the individual responses to TRAIL in a clonal population of HeLa cells using live-cell microscopy and computational modelling. We show that the cellular mitochondrial content determines the apoptotic fate and modulates the time to death, cells with higher mitochondrial content are more prone to die. We find that all apoptotic protein levels are modulated by the mitochondrial content. Modelling the apoptotic network, we demonstrate that these correlations, and especially the differential control of anti- and pro-apoptotic protein pairs, confer mitochondria a powerful discriminatory capacity of apoptotic fate. We find a similar correlation between the mitochondria and apoptotic proteins in colon cancer biopsies. Our results reveal a different role of mitochondria in apoptosis as the global regulator of apoptotic protein expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Death / genetics
  • Gene Expression / drug effects
  • Gene Expression / genetics*
  • HeLa Cells
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Models, Genetic
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology


  • Apoptosis Regulatory Proteins
  • Reactive Oxygen Species
  • TNF-Related Apoptosis-Inducing Ligand