A 25+ Year Journey on Yeast-Regulated Cell Death Research

More than 25 years ago, researchers began to question whether budding yeast, a unicellular eukaryote, could undergo a cell death process similar to mammalian apoptosis. We and others pursued this inquiry to enhance our understanding of yeast's endogenous cell death mechanisms and to exploit yeast as a simple cell model for potential translation to and from the mammalian apoptosis field. Initially, there was skepticism, as apoptosis was thought to be exclusive to multicellular organisms, and key regulators of mammalian apoptosis were absent from yeast. Over the years, the study of cell death using different cell/organism models has evolved, with cell death processes now broadly categorized into accidental cell death (ACD) and regulated cell death (RCD). According to this classification, unlike ACD, RCD can be pharmacologically and genetically controlled. This chapter provides a historical retrospective of yeast RCD (yRCD) research, examining conserved molecular components, organelles, signaling pathways, and posttranslational modifications that regulate cellular commitment to death. By revisiting early interpretations in light of contemporary evidence, we highlight how several initial dogmas have been refined or overturned, while conceptual and methodological challenges remain. We anticipate that less explored and novel experimental approaches and technologies, particularly those offering temporal, single-cell, and systems-level resolution, will continue to advance the field, enabling relevant biotechnological and biomedical applications and helping to address current challenges associated with sustainable development.