Figure 13.

A model for a mechanism underlying POA-induced liponecrotic PCD in yeast. Exogenously added POA is incorporated into POA-containing phospholipids (PL) that amass in the endoplasmic reticulum (ER) membrane, mitochondrial membranes and the plasma membrane (PM). The buildup of the POA-containing PL in the PM reduces the level of phosphatidylethanolamine (PE) in its outer leaflet, thereby increasing PM permeability for small molecules and committing yeast to liponecrosis. The excessive accumulation of POA-containing PL in mitochondrial membranes impairs mitochondrial functionality and causes the excessive production of reactive oxygen species (ROS) in mitochondria. The resulting rise in cellular ROS above a critical level contributes to the commitment of yeast to liponecrosis by: (1) oxidatively damaging numerous cellular organelles, thereby triggering their autophagic degradation; and (2) oxidatively damaging various cytosolic proteins, thus impairing cellular proteostasis. Several processes in yeast exposed to POA can protect cells from liponecrosis. They include: (1) POA oxidation in peroxisomes, which reduces the flow of POA into PL synthesis pathways; (2) POA incorporation into triacylglycerols (TAG, a major form of neutral lipids), which prevents the excessive accumulation of POA-containing PL in cellular membranes; (3) mitophagy, a selective autophagic degradation of dysfunctional mitochondria, which sustains a population of functional mitochondria needed for POA incorporation into TAG; and (4) a degradation of damaged, dysfunctional and aggregated cytosolic proteins, which enables the maintenance of cellular proteostasis. Activation arrows and inhibition bars denote pro-death processes (displayed in red color) or pro-survival processes (displayed in blue color) for POA-induced liponecrotic PCD.