title: Mechanism of liponecrosis, a distinct mode of programmed cell death.
abstract: An exposure of the yeast Saccharomyces cerevisiae to exogenous palmitoleic acid (POA) elicits "liponecrosis," a mode of programmed cell death (PCD) which differs from the currently known PCD subroutines. Here, we report the following mechanism for liponecrotic PCD. Exogenously added POA is incorporated into POA-containing phospholipids that then amass in the endoplasmic reticulum membrane, mitochondrial membranes and the plasma membrane. The buildup of the POA-containing phospholipids in the plasma membrane reduces the level of phosphatidylethanolamine in its extracellular leaflet, thereby increasing plasma membrane permeability for small molecules and committing yeast to liponecrotic PCD. The excessive accumulation of POA-containing phospholipids in mitochondrial membranes impairs mitochondrial functionality and causes the excessive production of reactive oxygen species in mitochondria. The resulting rise in cellular reactive oxygen species above a critical level contributes to the commitment of yeast to liponecrotic PCD by: (1) oxidatively damaging numerous cellular organelles, thereby triggering their massive macroautophagic degradation; and (2) oxidatively damaging various cellular proteins, thus impairing cellular proteostasis. Several cellular 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 phospholipid synthesis pathways; (2) POA incorporation into neutral lipids, which prevents the excessive accumulation of POA-containing phospholipids in cellular membranes; (3) mitophagy, a selective macroautophagic degradation of dysfunctional mitochondria, which sustains a population of functional mitochondria needed for POA incorporation into neutral lipids; and (4) a degradation of damaged, dysfunctional and aggregated cytosolic proteins, which enables the maintenance of cellular proteostasis.
authors.affiliation: a Department of Biology ; Concordia University ; Montreal , QC Canada.
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Richard
authors.forename: Adam
authors.initials: A
authors.lastname: Beach
authors.forename: Amanda
authors.initials: A
authors.lastname: Piano
authors.forename: Anna
authors.initials: A
authors.lastname: Leonov
authors.forename: Rachel
authors.initials: R
authors.lastname: Feldman
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Burstein
authors.forename: Pavlo
authors.initials: P
authors.lastname: Kyryakov
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gomez-Perez
authors.forename: Anthony
authors.initials: A
authors.lastname: Arlia-Ciommo
authors.forename: Stefanie
authors.initials: S
authors.lastname: Baptista
authors.forename: Cory
authors.initials: C
authors.lastname: Campbell
authors.forename: Daniel
authors.initials: D
authors.lastname: Goncharov
authors.forename: Sonia
authors.initials: S
authors.lastname: Pannu
authors.forename: Dimitri
authors.initials: D
authors.lastname: Patrinos
authors.forename: Behnaz
authors.initials: B
authors.lastname: Sadri
authors.forename: Veronika
authors.initials: V
authors.lastname: Svistkova
authors.forename: Andrew
authors.initials: A
authors.lastname: Victor
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Titorenko
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity*; D008563:Membrane Lipids / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D005229:Fatty Acids, Monounsaturated; D008563:Membrane Lipids; C008757:palmitoleic acid
keywords: CFU, colony forming units; CL, cardiolipin; Cvt, cytoplasm-to-vacuole pathway; ER, endoplasmic reticulum; IMM, inner mitochondrial membrane; LD, lipid droplets; NL, neutral lipids; PA, phosphatidic acid; PC, phosphatidylcholine; PCD, programmed cell death; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PL, phospholipids; PM, plasma membrane; POA, palmitoleic acid; PS, phosphatidylserine; ROS, reactive oxygen species; TAG, triacylglycerols; WT, wild-type; apoptosis; autophagy; cellular proteostasis; lipid metabolism in cellular organelles; mechanisms of programmed cell death; mitochondria,; mitophagy; plasma membrane; signal transduction; yeast