Acid stress causes resistance to acetic acid-induced regulated cell death (AA-RCD) in budding yeast, resulting in catalase activation. In order to explore the molecular determinants of evasion of AA-RCD triggered by acid stress adaptation, we studied the involvement and the possible interplay of the master regulator of transcription high-osmolarity glycerol 1 (HOG1) and RTG2, a positive regulator of the RTG-dependent mitochondrial retrograde signaling. Viability, DNA fragmentation, and ROS accumulation have been analyzed in wild-type and mutant cells lacking HOG1 and/or RTG2. Catalase activity and transcription of CTT1 and CTA1, coding the cytosolic and peroxisomal/mitochondrial catalase, respectively, as well as Hog1 phosphorylation, were also analyzed. Our results show that HOG1 is essential for resistance to AA-RCD and its activation results in the upregulation of CTT1, but not CTA1, transcription during acid stress adaptation. RTG2 is required for Hog1-dependent CTT1 upregulation upon acid stress, despite failure of RTG pathway activation. We give evidence that Rtg2 has a cytoprotective role and can act as a general cell stress sensor independent of Rtg1/3-dependent transcription.