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    Apoptosis

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    iamaakashchoudhary
    Apoptosis, or programmed cell death, is an essential process for multicellular organisms where cells actively initiate and carry out their own death. It is important for development, homeostasis, and protection by removing damaged or infected cells. The cell undergoes condensation, fragmentation into apoptotic bodies, and is quickly cleared by phagocytes without inducing inflammation. Apoptosis can be triggered through withdrawal of survival signals or receipt of death signals and involves caspase activation through the intrinsic or extrinsic pathway, ultimately degrading proteins and nucleic acids in a controlled manner. In contrast, necrosis is unregulated cell death due to external factors that induces swelling and rupturing of the cell, releasing intracellular contents and eliciting inflammation.

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    Apoptosis

    Uploaded by

    iamaakashchoudhary
    9 views33 pages
    Apoptosis, or programmed cell death, is an essential process for multicellular organisms where cells actively initiate and carry out their own death. It is important for development, homeostasis, and protection by removing damaged or infected cells. The cell undergoes condensation, fragmentation into apoptotic bodies, and is quickly cleared by phagocytes without inducing inflammation. Apoptosis can be triggered through withdrawal of survival signals or receipt of death signals and involves caspase activation through the intrinsic or extrinsic pathway, ultimately degrading proteins and nucleic acids in a controlled manner. In contrast, necrosis is unregulated cell death due to external factors that induces swelling and rupturing of the cell, releasing intracellular contents and eliciting inflammation.

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    Apoptosis, or programmed cell death, is an essential process for multicellular organisms where cells actively initiate and carry out their own death. It is important for development, homeostasis, and protection by removing damaged or infected cells. The cell undergoes condensation, fragmentation into apoptotic bodies, and is quickly cleared by phagocytes without inducing inflammation. Apoptosis can be triggered through withdrawal of survival signals or receipt of death signals and involves caspase activation through the intrinsic or extrinsic pathway, ultimately degrading proteins and nucleic acids in a controlled manner. In contrast, necrosis is unregulated cell death due to external factors that induces swelling and rupturing of the cell, releasing intracellular contents and eliciting inflammation.

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    © All Rights Reserved
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    9 views33 pages

    Apoptosis

    Uploaded by

    iamaakashchoudhary
    Apoptosis, or programmed cell death, is an essential process for multicellular organisms where cells actively initiate and carry out their own death. It is important for development, homeostasis, and protection by removing damaged or infected cells. The cell undergoes condensation, fragmentation into apoptotic bodies, and is quickly cleared by phagocytes without inducing inflammation. Apoptosis can be triggered through withdrawal of survival signals or receipt of death signals and involves caspase activation through the intrinsic or extrinsic pathway, ultimately degrading proteins and nucleic acids in a controlled manner. In contrast, necrosis is unregulated cell death due to external factors that induces swelling and rupturing of the cell, releasing intracellular contents and eliciting inflammation.

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    of 33

    APOPTOSIS

    INTRODUCTION

    Cell death by injury


    -Mechanical damage
    -Exposure to toxic chemicals
    Cell death by suicide
    -Internal signals
    -External signals
    Conted…..

    Apoptosis or programmed cell death, is carefully


    coordinated collapse of cell, protein degradation ,
    DNA fragmentation followed by rapid engulfment
    of corpses by neighbouring cells. (Tommi, 2002)

    Essential part of life for every multicellular


    organism from worms to humans. (Faddy et al.,1992)

    Apoptosis plays a major role from embryonic


    development to senescence.
    Why should a cell commit suicide?
    Apoptosis is needed for proper development
    Examples:
    – The resorption of the tadpole tail
    – The formation of the fingers and toes of the fetus
    – The sloughing off of the inner lining of the uterus
    – The formation of the proper connections between neurons in the brain

    Apoptosis is needed to destroy cells


    Examples:
    – Cells infected with viruses
    – Cells of the immune system
    – Cells with DNA damage
    – Cancer cells
    What makes a cell decide to commit suicide?

    Withdrawal of positive signals


    examples :
    – growth factors for neurons
    – Interleukin-2 (IL-2)

    Receipt of negative signals


    examples :
    – increased levels of oxidants within the cell
    – damage to DNA by oxidants
    – death activators :
    • Tumor necrosis factor alpha (TNF-)
    • Lymphotoxin (TNF-β)
    • Fas ligand (FasL)
    Apoptosis – Programmed Cell Death
    Why? Developmental
    Protective (destroy cells that are a threat)
    infected with virus
    turn off immune response
    DNA damaged cells
    cancer
    Necrosis vs. Apoptosis

    Necrosis Apoptosis
    • Cellular swelling • Cellular condensation
    • Membranes are broken • Membranes remain intact
    • ATP is depleted • Requires ATP
    • Cell lyses, eliciting an • Cell is phagocytosed, no
    inflammatory reaction tissue reaction
    • DNA fragmentation is • Ladder-like DNA
    random, or smeared fragmentation
    • In vivo, whole areas of • In vivo, individual cells
    the tissue are affected appear affected
    NECROSIS Vs APOPTOSIS

    Wilde, 1999
    Death by Injury vs. Death by Suicide
    (Necrosis vs. Apoptosis)
    Tumor Suppressor Genes: when tumor suppressor genes are inactivated, the inhibitory
    activity is lost, and unprogrammed cell proliferation can begin
    .
    human TP53 gene is at
    chromosome location 17p13.1.
    Individuals who inherit one mutant
    copy of TP53 develop
    Li–Fraumeni syndrome, a rare form
    of cancer that
    is an autosomal dominant trait
    because the cancer develops
    when the second copy of TP53
    becomes mutated.
    What makes a cell commit suicide?
    withdrawal of positive signals (growth factors, Il-2)
    receipt of negative signals (increased levels of oxidants, DNA damage via X-ray
    or UV light, chemotherapeutic drugs, accumulation of improperly folded
    proteins, death activators such as: TNF-a, TNF-b, Fas/FasL)

    Steps in apoptosis:
    the decision to activate the pathway;
    the actual "suicide" of the cell;
    engulfment of the cell remains by specialized immune cells called phagocytes;
    degradation of engulfed cell.
    The actual steps in cell death require:
    condensing of the cell nucleus and breaking it into pieces
    condensing and fragmenting of cytoplasm into membrane bound apoptotic
    bodies;
    breaking chromosomes into fragments containing multiple number of
    nucleosomes (a nucleosome ladder)
    Apoptosis Triggered via Two Pathways
    Intrinsic or mitochondrial pathway
    Extrinsic or death receptor pathway
    What is a Caspase?
    • Single chain of pro-enzymes
    • cysteine-aspartic proteases are a family of protease
    enzymes helps in programmed cell death
    • Contains an N-terminal domain, a small subunit and a
    large subunit (similar to a ribosome)
    • 3 Types of Caspases
    • Inflammatory Caspases: -1, -4, and -5
    • Initiator Caspases: -2, -8, -9, and -10
    – Long N-terminal domain
    – Interact with effector caspases
    • Effector Caspases: -3, -6, and -7
    – Little to no N-terminal domain
    – Initiate cell death
    Extrinsic or Death • Binding of Fas by FasL
    Receptor Pathway induces recruitment of FADD
    to the cytoplasmic tail of Fas
    • The opposite end of FADD
    contains a death effector
    domain (hatched boxes);
    recruitment of either
    procaspase-8 or c-FLIP
    • Caspase-8 can cleave Bid
    • truncated Bid (tBid) can
    inactivate Bcl-2 in the
    mitochondrial membrane.
    • This allows the escape of
    cytochrome c, which clusters
    with Apaf-1 and caspase-9 in
    the presence of dATP to
    activate caspase-9.
    • Smac/DIABLO is also released
    from the mitochondria and
    inactivates inhibitors of
    apoptosis (IAPs).
    • breakdown of several
    cytoskeletal proteins and
    degradation of the inhibitor of
    caspase-activated DNase
    (ICAD).
    In a healthy cell, the outer membranes of its
    mitochondria display the protein Bcl-2 on
    their surface.
    Internal damage to the cell (e.g., from
    reactive oxygen species) causes
    Bcl-2 to activate a related protein, Bax, which
    punches holes in the outer mitochondrial
    membrane, causing
    cytochrome c to leak out.
    The released cytochrome c binds to the
    protein Apaf-1 ("apoptotic protease activating
    factor-1").
    Using the energy provided by ATP,
    these complexes aggregate to form
    apoptosomes.
    The apoptosomes bind to and activate
    caspase-9.
    Caspase-9 is one of a family of over a dozen
    caspases. They are all proteases. They get
    their name because they cleave proteins —
    mostly each other — at aspartic acid (Asp)
    residues).
    Caspase-9 cleaves and, in so doing,
    activates other caspases (caspase-3 and -7).
    The activation of these "executioner"
    caspases creates an expanding cascade of
    proteolytic activity (rather like that in blood
    clotting and complement activation) which
    leads to digestion of structural proteins in the
    cytoplasm, degradation of chromosomal
    DNA, and phagocytosis of the cell.
    •Cytoplasm shrinks due to
    cleavage of nuclear lamins
    and actin
    •Chromatin is broken
    down as nucleus
    condenses (often
    horseshoe shaped
    •Cells shrink making an
    easy meal for phagocytes
    •Cells undergo plasma
    membrane changes –
    move phosphatidylserine
    from inner to outer leaflet
    of the membrane; attracts
    macrophages

    video

    Jazzy video
    Necrosis
    Trauma (toxic chemicals, mechanical injury, heat, hypoxia)
    Loss of ability to regulate internal environment
    Ca2+ influx accompanied by swelling
    Alteration of protein activity
    calpain
    cathepsin
    caspase
    Production of toxic compounds
    (activation of cyclooxygenases)
    arachadonic acid
    prostaglandins
    eicosanoids

    Inflammation

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