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Active Ras2 in mitochondria promotes regulated cell death in a cAMP/PKA pathway-dependent manner in budding yeast

Barbara Bonomelli1, Stefano Busti1, Enzo Martegani1

  • 1Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.

FEBS Letters
|December 17, 2022
PubMed

Insights

Aberrant Ras accumulation in mitochondria correlates with apoptosis. This study identifies Ras2 as a key GTPase in yeast cell death, while Ras1 may promote survival, both impacting the cAMP/PKA pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Yeast Genetics

Background:

  • Aberrant accumulation of activated Ras in mitochondria correlates with increased apoptosis.
  • Trehalose-6P-synthase deficiency triggers apoptosis in Saccharomyces cerevisiae and induces active Ras protein localization in mitochondria.

Purpose of the Study:

  • To confirm the correlation between mitochondrial Ras localization and apoptosis.
  • To elucidate the roles of Ras1 and Ras2 GTPases in yeast apoptosis and survival.
  • To investigate the involvement of the cAMP/PKA pathway in mitochondrial Ras-mediated apoptosis.

Main Methods:

  • Characterization of Saccharomyces cerevisiae mutants (ras1Δ, ras2Δ, gpa2Δ, cyr1Δ).
  • Analysis of active Ras protein localization in mitochondria.
  • Assessment of apoptosis induction and cell survival pathways.

Main Results:

  • Lack of trehalose-6P-synthase induces active Ras localization in mitochondria.
  • Active Ras2 GTPases accumulate in mitochondria under pro-apoptotic stimulus (acetic acid), implicating them in regulated cell death.
  • Active Ras1 proteins are constitutively mitochondrial, suggesting a pro-survival role.
  • Compromised cAMP/PKA pathway (gpa2Δ, cyr1Δ mutants) reveals that active mitochondrial Ras proteins promote apoptosis via this pathway.

Conclusions:

  • Active Ras2 is a key mediator of yeast apoptosis, localized to mitochondria.
  • Active Ras1 may function in a pro-survival pathway within mitochondria.
  • The cAMP/PKA pathway is essential for mediating apoptosis induced by active mitochondrial Ras proteins.
Keywords:
S. cerevisiaeROSacetic acidapoptosismitochondriaregulated cell death

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