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

Madhavika N Serasinghe1, Shira Y Wieder1, Thibaud T Renault2

  • 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.

Molecular Cell
|February 7, 2015
PubMed

Insights

Mitochondrial division protein DRP1 is key in cancer cell transformation. Inhibiting DRP1 blocks RAS-driven cancer and impacts MAPK signaling, offering new therapeutic strategies.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Mitochondrial Dynamics

Background:

  • Mitochondrial division is vital for cell function but its role in cancer is unclear.
  • Oncogenic mutations can alter cellular processes, including mitochondrial dynamics.

Purpose of the Study:

  • To investigate the role of mitochondrial division protein DRP1 in oncogenic transformation.
  • To explore the link between MAPK signaling, DRP1, and mitochondrial dysfunction in cancer.

Main Methods:

  • Studied effects of oncogenic RAS(G12V) on mitochondrial dynamics.
  • Analyzed DRP1's role in RAS-mediated transformation and MAPK-mutated cell lines.
  • Investigated ERK1/2 phosphorylation of DRP1 at serine 616.

Main Results:

  • RAS(G12V) transformation selects for DRP1, essential for mitochondrial division.
  • Loss of DRP1 prevents RAS-induced mitochondrial dysfunction and transformation.
  • MAPK pathway inhibition causes DRP1 loss, mitochondrial hyper-fusion, and increased metabolism.
  • ERK1/2 phosphorylation of DRP1 at S616 links these phenotypes and distinguishes BRAF mutations.

Conclusions:

  • Mitochondrial division protein DRP1 is a critical regulator of cancer cell transformation.
  • DRP1 phosphorylation by ERK1/2 is a key mechanism in oncogenic transformation.
  • Targeting DRP1 offers potential for novel cancer chemotherapeutics.

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