Mechanisms of Disease 2: Cell Damage and Cell Death

Question 1

Explain the range and nature of environmental and endogenous causes of cell and tissue damage

Answer 1

1) Physical Damage:

• Physical trauma, such as cuts, bruises, or broken bones, can directly cause cellular and tissue damage
• Radiation exposure, including UV radiation from the sun, can damage DNA and other cellular structures, leading to cell death or oncogenic mutations

2) Chemical Damage:

• Exposure to toxic chemicals can harm cells and tissues
• E.g. heavy metals can cause oxidative stress, and certain organic compounds can interfere with cellular function or DNA integrity
• Internally, errors in metabolism can lead to the accumulation of toxic compounds

3) Infectious Agents:

• Bacteria, viruses, parasites, and fungi can cause significant cell and tissue damage
• They can disrupt cellular processes, hijack cellular machinery, stimulate harmful immune responses (inflammation), or produce toxins

4) Immunological Damage:

• Autoimmune disorders, where the immune system mistakenly attacks the body’s own cells, can result in cell and tissue damage
• Overactive immune responses, such as chronic inflammation, can also be harmful

5) Genetic Factors:

• Genetic mutations can disrupt normal cellular functions, leading to cellular and tissue damage

6) Nutritional Factors:

• Deficiencies in certain vitamins and minerals can interfere with cellular functions, while excess intake of certain nutrients can contribute to obesity and associated metabolic disorders

7) Aging:

• As cells and tissues age, they accumulate damage that can impair their function
• This can result from a variety of factors, including oxidative stress, telomere shortening, and the accumulation of DNA mutations

8) Oxidative Stress:

• Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (free radicals) and the body’s ability to counteract or detoxify their harmful effects through neutralization by antioxidants
• This can lead to cell damage and death

9) Hypoxia:

• Lack of oxygen (hypoxia) can cause cell injury and death. Oxygen is critical for cellular respiration and energy production in the mitochondria

Question 2

Explain the biochemical and morphological differences between cells undergoing necrosis and apoptosis

Answer 2

Necrosis:

Necrosis is a form of cell death that occurs due to injury, infection, or the failure of blood supply, which includes factors such as toxins, hypoxia, or trauma

It is an uncontrolled and passive process that leads to a loss of cell membrane integrity, causing the release of intracellular contents, which can trigger an inflammatory response in the body

Biochemical Features:

• Increased membrane permeability
• Disruption of membrane integrity
• Degradation of proteins and organelles
• ATP depletion

Morphological Features:

• Early cellular swelling
• Disruption of the plasma and organelle membranes
• Clumping and random fragmentation of chromatin
• Release of cellular contents into the surrounding tissue

Apoptosis:

a regulated and programmed process of cell death that occurs during development, aging, or as a defence mechanism such as removing infected, damaged, or cancerous cells

It is a controlled process that does not usually elicit an inflammatory response as the cell’s contents are packaged into small vesicles (apoptotic bodies) that are removed by phagocytic cells

Biochemical Features of Apoptosis:

• Activation of a class of proteins called caspases; for executing apoptosis
• Protein and DNA fragmentation
• Externalisation of phosphatidylserine, a signal for phagocytic cells
• Retention of ATP for energy-dependent steps of apoptosis

Morphological Features of Apoptosis:

• Cell shrinkage and condensation
• Chromatin condensation (pyknosis)
• DNA fragmentation
• Formation of apoptotic bodies
• Phagocytosis of apoptotic bodies by surrounding cells

Question 3

Define the exogenous and endogenous initiators of apoptosis

Answer 3

Exogenous (extrinsic) Pathway of Apoptosis:

• The extrinsic pathway is triggered by external signals. These signals are typically ‘death ligands’ that bind to ‘death receptors’ on the cell surface
• E.g. Fas ligand binding to the Fas receptor (CD95), which belongs to the tumor necrosis factor (TNF) receptor superfamily
• Once the Fas ligand binds to the Fas receptor, it causes the receptor to cluster and form a death-inducing signaling complex (DISC)
• The DISC recruits and activates the initiator caspase, caspase-8
• Activated caspase-8 then goes on to activate the executioner caspases (caspase-3, -6, and -7), which orchestrate the cell death

Endogenous (intrinsic) Pathway of Apoptosis:

• activated by internal signals including DNA damage, oxidative stress, and ER stress
• involves the mitochondria and is regulated by the Bcl-2 family of proteins, which includes both pro-apoptotic (Bax, Bak, Bad) and anti-apoptotic members (Bcl-2, Bcl-xL)
• In response to apoptotic stimuli, the balance of these proteins shifts in favour of the pro-apoptotic members
• leading to mitochondrial outer membrane permeabilisation (MOMP)
• MOMP results in the release of cytochrome c from the mitochondria into the cytosol
• In the cytosol, cytochrome c, along with apoptotic protease activating factor-1 (Apaf-1) and pro-caspase-9, forms the apoptosome
• The apoptosome facilitates the cleavage and activation of caspase-9, which in turn activates the executioner caspases (caspase-3, -6, and -7) leading to cell death

Can be interconnected, i.e. caspase-8 (activated by the extrinsic pathway) can cleave the Bcl-2 family member Bid to create truncated Bid (tBid). tBid can then engage the intrinsic pathway