Regulation of Cell Death Induced by Acetic Acid in Yeasts

Abstract

Acetic acid has long been considered a molecule of great interest in the yeast research field. It is mostly recognized as a by-product of alcoholic fermentation or as a product of the metabolism of acetic and lactic acid bacteria, as well as of lignocellulosic biomass pretreatment. High acetic acid levels are commonly associated with arrested fermentations or with utilization as vinegar in the food industry. Due to its obvious interest to industrial processes, research on the mechanisms underlying the impact of acetic acid in yeast cells has been increasing. In the past twenty years, a plethora of studies have addressed the intricate cascade of molecular events involved in cell death induced by acetic acid, which is now considered a model in the yeast regulated cell death field. As such, understanding how acetic acid modulates cellular functions brought about important knowledge on modulable targets not only in biotechnology but also in biomedicine. Here, we performed a comprehensive literature review to compile information from published studies performed with lethal concentrations of acetic acid, which shed light on regulated cell death mechanisms. We present an historical retrospective of research on this topic, first providing an overview of the cell death process induced by acetic acid, including functional and structural alterations, followed by an in-depth description of its pharmacological and genetic regulation. As the mechanistic understanding of regulated cell death is crucial both to design improved biomedical strategies and to develop more robust and resilient yeast strains for industrial applications, acetic acid-induced cell death remains a fruitful and open field of study.

Keywords: acetic acid; apoptosis; biotechnology; mitochondria; regulated cell death; signaling pathways; vacuole.

FIGURE 1

Current knowledge on the hallmarks of AA-RCD. When yeast cells are treated with lethal concentrations of acetic acid, a regulated cell death process characterized by typical mammalian apoptotic markers, highlighted in blue, can be triggered depending on the concentration. pHi, intracellular pH; pHv, vacuolar pH; pHm, mitochondrial pH; VMP, vacuolar membrane permeabilization; MOMP, mitochondrial outer membrane permeabilization; Cyt c, cytochrome c; Ψp, plasma membrane potential; Ψm, mitochondrial membrane potential.

FIGURE 2

Schematic diagram of the signaling pathways involved in AA-RCD in yeast. Arrows indicate activation of proteins or promotion of a post-translational modification; lines with bars indicate their inhibition/inactivation. Different MAPK signaling pathways or clusters are color-coded as shown. The phenotypes resulting from the deletion or overexpression of the corresponding protein-coding gene are represented with symbols. The symbols are: triangle with a plus (gene deletion confers resistance), triangle with a minus (gene deletion confers sensitivity), square with a plus (protein overexpression confers resistance), and square with a minus (protein overexpression confers sensitivity). Phosphorylation is represented with a circle with a P. Some phenotypes were not included due to contradictory data among the studies. For clarity, despite the number of different proteins and signaling cascades displayed in this scheme, not all players, connections between the pathways and direct targets of the proteins are shown.