Cell Damage and Death Flashcards
What is cell death caused by?
Necrosis: most common, from ischemia, trauma, chemical injury- accidental
Apoptosis: Designed cell death
Autophagic cell death: degrades normal proteins involved in cellular remodeling. Removes abnormal proteins, eg death of breast cancer cells induced by Tamoxifen.
Describe the process of necrosis
Energy deprivation causes changes. (e.g. cells unable to make ATP bc no 02)
Cells swell due to water influx (ATP needed for ion pumps to work).
Enzymes from ruptured lysosomes destroy organelles and nuclear material
Cellular debris stimulates inflammatory response
Describe the nuclear changes in necrosis
What are the cytoplasmic and biochemical changes in necrosis?
Give examples of what is released
Cytoplasmic: Opacification=denaturation of proteins with aggregation.
Complete digestion of cells causing cell to liquify
Biochem: enzyme and protein release, eg creatine kinase or myoglobin
What clinical problems are associated with cell death? Describe the condition and what is released in each.
Muscular dystrophy. Damaged muscles release creatine kinase and lactate dehydrogenase (M3 and M3H isoforms).
Heart attack. Damaged muscles release lactate dehydrogenase (H3 and H3M).
Bone and liver disease. Damaged tissues release alkaline phosphatase and lactate dehydrogenase.
Haemolytic anaemias. Damaged RBCs release Lactate Dehydrogenase 1 and 2.
Explain the types of necrosis and give specific examples for each type
How would some of these look like under a microscope?
Coagulative: due to hypoxia. Cell outlines remain after death, seen by light microscopy (MI, infarct spleen).
Liquefactive: cellular destruction + pus formation (e.g. pneumonia).
Caseous: mix of coagulative + liquefactive, eg TB
Fatty: from lipase action on fatty tissues (eg. acute pancreatitis).
Fibrinoid: immune-mediated vascular damage. Fibrin-like deposits in artery walls, looks smudgy on light microscopy.
2 types of apoptosis: intrinsic and extrinsic.
Explain intrinsic apoptosis, what occurs, what is it due to, what changes?
DNA damage – p53-dependent pathway
Interruption of the cell cycle
Inhibition of protein synthesis
Happens due to viral Infection
Change in redox state
2 types of apoptosis: intrinsic and extrinsic.
Explain extrinsic apoptosis
Withdrawal of growth factors (e.g. IL-3)
Occurs due to extracellular signals (e.g. TNF)
Can be induced by T cell or NK (Natural Killer) (e.g. Granzyme)
What are capases?
Caspases are Cysteine Proteases. Most proteases need activation. This activation initiates apoptosis
Caspase X is first activated by being cleaved and then it cleaves procaspase Y to activate it. This continues in a caspase cascade.
What changes does caspase activation lead to?
What do blebs contain?
Caspase activation changes the cell, eg shrinkage, chromatin condensation, DNA fragmentation, plasma membrane blebbing
Blebs contain organelles which bled off in vesicles and are phagocytosed by macrophages
What does this show?
Necrosis: cell burst haphazardly, DNA denatured + liquefied even down to nucleosomes. Smear appearance as many fragments
Apoptosis: specific proteins degraded in controlled way, nucleosome preserved = ladder appearance
How are caspases activated in intrinsic vs extrinsic apoptosis?
Extrinsic: Induced proximity, eg: in response to receptor dimerization upon ligand binding
Intrinsic: Cytochrome C release from the mitochondria
Describe Ligand induced dimerization with TNF, linked with extrinsic apoptosis
TNF forms death inducing signal complex (DISC)
TNF binds TNF receptor, which brings receptor molecules juntos
Receptors have death domain on inside = recruit death adaptor protein (FADD) to complex
Death adaptor protein recruit multiple procaspases
Procaspases cleave each other to generate active caspase (initiator caspase). This begins apoptosis cascade
What is cytochrome c- when and where is it released, how does it help apoptosis?
Released in response to oxidative stress by a “permeability transition”
Cytochrome C released into cytosol binds apoptotic protease activating factor (APAF). This recruits caspase
So 2 cytochrome C bind 2 APAF which bind 2 caspases bringing them both together =autoproteolysis
Describe the regulation of cytochrome C, linked with intrinsic apoptosis
Cytochrome C released via family of proteins which form dimers:
Bcl-2, bcl-XL = anti apoptotic.
Bac, bad, bid = pro apoptotic
Pro apoptotic proteins form pores on mt membrane, allowing cytochrome C to come out
Normally survival signals in cell phosphorylate bad so it cannot bind bcl-2. Bcl-2 stays in pore
When survival signals stop, bad ya no phosphorylated= binds bcl-2 removing it from pore = apoptosis
