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Aging Genome 1.DNA damage 2.Epigenetic shifts 3.Telomere shortening Cellular level 1.Mitochondria: ROS, DNA damage, other 2.Misfolded proteins 3.Dysfunctional stem cells Organismal level 1.Autoimmune, other defects in immune system 2.Defective signaling

Apoptosis Two basic steps: commitment and execution Commitment depends on interplay between various signals Bax & Bcl2 have opposite effects 2 main pathways: extrinsic & intrinsic

Procaspase 8 binds FADD Procaspase 8 is processed to caspase 8 = initiator caspase Caspase 8 converts procaspase 3 to active form = executioner Caspase-3 & CAD execute the cell

Intrinsic pathway Usually Bcl-2 protects mito Intracellular damage activates Bad or Bax

Apoptosis Usually Bcl-2 protects mito Intracellular damage activates Bad or Bax Bad/Bax releases cyt c & AIF

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF Cyt c, Apaf-1 & procaspase-9 form complex = apoptosome

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF Cyt c, Apaf-1 & procaspase-9 form complex = apoptosome Apoptosome processes procaspase -9 to caspase-9 = initiator caspase

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF Cyt c, Apaf-1 & procaspase-9 form complex = apoptosome Apoptosome processes procaspase -9 to caspase-9 = initiator caspase Caspase-9 converts caspase 3 to active form = executioner

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF Cyt c, Apaf-1 & procaspase-9 form complex = apoptosome Apoptosome processes procaspase -9 to caspase-9 = initiator caspase Caspase-9 converts caspase 3 to active form = executioner Caspase 3 & CAD execute the cell

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF AIF induces CAD

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF AIF induces CAD Destroys DNA

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF AIF induces CAD Destroys DNA Flips PS outside

Apoptosis Intracellular damage activates Bad/Bax Bad/Bax release cyt c & AIF AIF induces CAD Destroys DNA Flips PS outside Phagocytic cells eat vesicles with external PS

Apoptosis Two basic steps: commitment and execution Commitment depends on interplay between various signals TNF often stimulates recovery instead!

Apoptosis in immunity PD1 receptor on T cells blocks apoptosis Binds PDL1 or PDL2 presented by other cells, including tumors

Apoptosis in immunity PD1 receptor on T cells blocks apoptosis Binds PDL1 or PDL2 presented by other cells, including tumors PDL1 inhibitors are a new class of cancer drug

Autophagy Intracellular recycling process – lysosomes (animals); vacuoles (plants)

Autophagy Intracellular recycling process – lysosomes (animals); vacuoles (plants) Removes misfolded proteins, bad organelles, intracell pathogens

Autophagy Intracellular recycling process – lysosomes (animals); vacuoles (plants) Removes misfolded proteins, bad organelles, intracell pathogens Promotes survival!

Autophagy Intracellular recycling process – lysosomes (animals); vacuoles (plants) Removes misfolded proteins, bad organelles, intracell pathogens Promotes survival! Reallocates nutrients to vital processes!

Autophagy Removes misfolded proteins, bad organelles, intracell pathogens Promotes survival! Reallocates nutrients to vital processes! Best way to get rid of bad mito w/o killing cell!

Autophagy Removes misfolded proteins, bad organelles, intracell pathogens Promotes survival! Reallocates nutrients to vital processes! Best way to get rid of bad mito w/o killing cell! Associated with increased longevity in caloric restriction

Autophagy Associated with increased longevity in caloric restriction Upregulated upon nutrient or growth factor deprivation

Autophagy Associated with increased longevity in caloric restriction Upregulated upon nutrient or growth factor deprivation Triggers PCD distinct from apoptosis if can’t cope No caspase or CAD, chromatin laddering Occurs inside lysosomes

Autophagy Triggers PCD distinct from apoptosis if can’t cope No caspase or CAD, chromatin laddering Occurs inside lysosomes Highly regulated!

Autophagy Triggers PCD distinct from apoptosis if can’t cope No caspase or CAD, chromatin laddering Occurs inside lysosomes Highly regulated! Mis-regulation associated with heart disease, diabetes and many more

Pyroptosis PCD associated with antimicrobial responses in inflammation

Pyroptosis PCD associated with antimicrobial responses in inflammation Toll-like receptors bind PAMPs, eg bacterial flagellins

Pyroptosis PCD associated with antimicrobial responses in inflammation Toll-like receptors bind PAMPs, eg bacterial flagellins Activated NOD-like receptors (NLRs) initiate assembly of pyroptosomeNOD-like receptors (NLRs)

Pyroptosis PCD associated with antimicrobial responses in inflammation Toll-like receptors bind PAMPs, eg bacterial flagellins Activated NOD-like receptors (NLRs) initiate assembly of pyroptosomeNOD-like receptors (NLRs) Pyroptosome activates Caspase-1

Pyroptosis PCD associated with antimicrobial responses in inflammation Toll-like receptors bind PAMPs, eg bacterial flagellins Activated NOD-like receptors (NLRs) initiate assembly of pyroptosomeNOD-like receptors (NLRs) Pyroptosome activates Caspase-1 Caspase-1 executes cell, Releasing PAMPs and cytokines

Pyroptosis PCD associated with antimicrobial responses in inflammation Toll-like receptors bind PAMPs, eg bacterial flagellins Activated NOD-like receptors (NLRs) initiate assembly of pyroptosomeNOD-like receptors (NLRs) Pyroptosome activates Caspase-1 Caspase-1 executes cell, Releasing PAMPs and Cytokines Reason for depletion of CD4 cells in AIDS

Necroptosis PCD associated with viral infections

Necroptosis PCD associated with viral infections Infected cells release TNF

Necroptosis PCD associated with viral infections Infected cells release TNF TNFR activates RIPK1 RIPK1 binds RIPK3 to form necrosome

Necroptosis PCD associated with viral infections Infected cells release TNF TNFR activates RIPK1 RIPK1 binds RIPK3 to form necrosome Necrosome activates MLKL which permeabilizes membranes

Necroptosis vs apoptosis Tend to inhibit each other, but do have overlap

Necroptosis vs apoptosis Tend to inhibit each other, but do have overlap Fail-safe for viruses that block apoptosis

Ferroptosis PCD dependent on intra-cellular iron Triggered by inhibition of cystine uptake

Ferroptosis PCD dependent on intra-cellular iron Triggered by inhibition of cystine uptake Reduced cystine uptake leads to the production of lethal lipid ROS

Ferroptosis PCD dependent on intra-cellular iron Triggered by inhibition of cystine uptake Reduced cystine uptake leads to the production of lethal lipid ROS Erastin etc trigger it

Ferroptosis PCD dependent on intra-cellular iron Triggered by inhibition of cystine uptake Reduced cystine uptake leads to the production of lethal lipid ROS Erastin etc trigger it Ferrostatin blocks it

Autophagy –Plant PCD Changes in shape and position of mitochondria (Mitochondrial morphology transition, MMT) Nuclear condensation Condensation of PM from cell wall Deregulated: dev’l defects, lethality (Scott & Logan, 2008, Plant Signaling & Behavior) MMT

Plant PCD In vegetative development In vegetative development –Suspensor degradation during embryo devt –Root cap devt and aerenchyma formation –Shaping of leaves Kawashima & Goldberg, 2009

PCD : Patterning in the lace plant leaf

PCD: aerenchyma formation Aerenchyma –Tissue for gas exchange –Aquatic species –Induced by submergence –Constitutive in rice: adaptation to flooding visible in all rice root types, except in small lateral roots Rebouillat et al., Rice 2009

Plant PCD In vegetative development –Tracheary element formation PCD-specific hydrolytic enzymes accumulate in vacuole S1-nuclease cysteine proteases  Vacuole enlarges  bursts  releases enzymes autolysis of cell contents & part of cw

Copyright ©2008 American Society of Plant Biologists Poulter, N. S., et al. Plant Physiol. 2008;146: Model for integration of cytoskeletal events triggered by SI Plant PCD In reproductive development – Tapetum and stomium degradation in anther – Female gametophyte devt – Flower senescence – Incompatibility reactions

Developed independently? Or evolved from a common ancestral cell death process? Some mol. components -- conserved e.g., PARP1, Bax-inhibitor-1, Defender against Apoptotic Death-1 PCD : Evolutionary perspective

Caspases –Cysteine proteases –Mol switches that activate c death Plants have proteases w/ caspase-like activities : Vacuolar processing enzymes (VPEs) PCD : Evolutionary perspective Gao et al., Plant Signaling & Behav. 2008

Mitochondria -- sensor of death signals & initiator of biochem processes leading to cell death PCD : role of mitochondrion

PCD : a role for chloroplasts PCD occurs indepen- dently of chloroplasts Chloroplasts – determine severity of & number of cells undergoing AL-PCD – ROS Elevated levels – physiological damage Signaling mol. Gao et al., Plant Signaling & Behav. 2008

Cell death due to biotic/abiotic stress Abiotic stresses: Temperature extremes Ozone Hypoxia Mediated by plant hormones Ethylene Jasmonic acid Salicylic acid Regulators: Reactive oxygen species (ROS): Superoxide anion radical Hydrogen peroxide (H 2 O 2 ) Nitric oxide (NO) Steffens and Sauter, Plant Cell, 2009