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

Previously, we showed that an aberrant accumulation of activated Ras in mitochondria correlates with an increase in apoptosis. In this article, we show that lack of trehalose-6P-synthase, known to trigger apoptosis in Saccharomyces cerevisiae, induces localization of active Ras proteins in mitochondria, confirming the above-mentioned correlation. Next, by characterizing the ras1 Delta and ras2 Delta mutants, we show that active Ras2 proteins, which accumulate in the mitochondria following addition of acetic acid (a pro-apoptotic stimulus), are likely the GTPases involved in regulated cell death, while active Ras1 proteins, constitutively localized in mitochondria, might be involved in a pro-survival molecular machinery. Finally, by characterizing the gpa2 Delta and cyr1 Delta mutants, in which the cAMP/PKA pathway is compromised, we show that active mitochondrial Ras proteins promote apoptosis through the cAMP/PKA pathway.

Automated summary

Previously, we found that an abnormal accumulation of activated Ras in mitochondria is associated with increased apoptosis. In this article, we confirm this correlation by showing that the lack of trehalose-6P-synthase, which triggers apoptosis in Saccharomyces cerevisiae, leads to the localization of active Ras proteins in mitochondria. Furthermore, we demonstrate that active Ras2 proteins, accumulated in mitochondria in response to acetic acid, are likely involved in regulated cell death, while constitutively localized Ras1 proteins in mitochondria may play a role in promoting cell survival. Finally, we reveal that active mitochondrial Ras proteins promote apoptosis through the cAMP/PKA pathway, demonstrated by characterizing the gpa2 Delta and cyr1 Delta mutants.