Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors

Mol Cell. 2015 Feb 5;57(3):521-36. doi: 10.1016/j.molcel.2015.01.003.


Mitochondrial division is essential for mitosis and metazoan development, but a mechanistic role in cancer biology remains unknown. Here, we examine the direct effects of oncogenic RAS(G12V)-mediated cellular transformation on the mitochondrial dynamics machinery and observe a positive selection for dynamin-related protein 1 (DRP1), a protein required for mitochondrial network division. Loss of DRP1 prevents RAS(G12V)-induced mitochondrial dysfunction and renders cells resistant to transformation. Conversely, in human tumor cell lines with activating MAPK mutations, inhibition of these signals leads to robust mitochondrial network reprogramming initiated by DRP1 loss resulting in mitochondrial hyper-fusion and increased mitochondrial metabolism. These phenotypes are mechanistically linked by ERK1/2 phosphorylation of DRP1 serine 616; DRP1(S616) phosphorylation is sufficient to phenocopy transformation-induced mitochondrial dysfunction, and DRP1(S616) phosphorylation status dichotomizes BRAF(WT) from BRAF(V600E)-positive lesions. These findings implicate mitochondrial division and DRP1 as crucial regulators of transformation with leverage in chemotherapeutic success.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Dynamins / genetics
  • Dynamins / metabolism*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • HT29 Cells
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Serine / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Protein Kinase Inhibitors
  • Serine
  • GTP Phosphohydrolases
  • ras Proteins
  • DNM1L protein, human
  • Dnm1l protein, mouse
  • Dynamins