AB2, L1: Cell Response to Injury and Damage _NEED TO EDIT

Given definition, answer w/ term

External Cell Injury

• Examples:

  • UV rays & x-irradiation

  • Temperature extremes

  • Chemicals and pollutants (e.g. environmental toxins & agricultural fertilizers)

  • Work & lifestyle choices (e.g. alcohol, smoking, cosmetics, cleaning products, & pharmaceuticals)

  • Pathogens & infectious agents

• Macromolecular Damage: o

Aerobic respiration

Internal Cell Injury

• Examples:

  • Metabolic process:

    • Creates intermediates that can be highly reactive and damaging

    • Can be hijacked by exogenous molecules (i.e. pharmaceutical agents, chemotherapies, & plant toxins)

• Macromolecular Damage: o

Reactive oxygen species (ROS)

• Definition: Collective term for unstable, highly reactive oxygen derivatives; often contain an unpaired electron

• Function: Plays an important role in cell signaling, metabolism, gene expression, and host defense mechanisms

  • Trigger oxidative attack of cellular macromolecules (e.g. cysteine)

  • Initiate chain reactions that promote significant damage

  • Critical for anti-microbial defenses

• Origin: 90% produced by electron transport chain

Guanine

What base in DNA is especially sensitive to damage?

Consequences of Macromolecular Damage

• Oxidation damage to guanine allows it to pair with Adenine, leading to mutations

• When this is replicated, this may introduce a T instead of a G

• Replication fixes a mutation within the daughter cells

X-rays and UVA

Consequences of Macromolecular Damage

• Triggers significants reactive oxygen species production and DNA oxidation

UVB

Consequences of Macromolecular Damage

• Crosslink adjacnet cystosine and thymine bases and pyrimidine dimers

X-rays and chemotherapetuics

Trigger signle and double DNA breaks

Chemotherapeutics and pollutants

Consequences of Macromolecular Damage

• Generate ROS, aldehydes, and DNA adducts

Protein oxidation leads to unfolding and irreversible damage:

Consequences of Macromolecular Damage

• Cystein oxidation causes non-native disulfide bond formation

Protein oxidation leads to unfolding and irreversible damage:

Consequences of Macromolecular Damage

• Irreversible oxidation causes protein misfolding and inactive. This exposed hydrophobic residues, which can then cause it to aggregate with other damaged proteins

• (protein aggregation and possible cleavage)

• Functional proteins (like enzymes) have enzyme active site, which is a prime site for oxidation/adduct. This can disrupt a signaling pathway and compromise function

Oxidation damage to membrane phospholipids

Consequences of Macromolecular Damage

• Unsaturated fatty acids and hydrophilic regions are prone to attack from ROS and reactive molecules

• This forms a lipid radicle, and steal electrons from its neighbors

• This causes a chain reaction of damage within the cell membrane called lipid peroxidation. This will reduce membrane fluidity, its permeability, and thickness

• It might also steal electrons from proteins within the membranes, which could generate highly reactive aldehydes which will attack other membranes proteins and neighboring DNA

Repaire damaged DNA & removed damaged DNA molecules and organelles

Respiratory burst

Intentional Creation of ROS

• Innate immune system will create NADPH oxidate and myeloperodixade enzymes, which will generate HUGE quantityies of superoxide and hypoclorite ROS upon stimulation

• Release ROS at sites of infections and within phagocytes to attack ad kill microbes

• it will kill them bc it’ll do the exact same damage to them that it does to our cells

Antioxidants

Protection Against Damage

• First line of defense to ROS

• Function: Donate electrons to neutralize radial species, rapidly regenerated by NADPH

• Examples:

  • Vitamin E – prevents lipid peroxidation

  • Vitamin C and glutathione – regenerate Vitamin E

Transition metal binding proteins

Protection Against Damage

• Function: Transport coppy and iron, restricting the body’s ability to propagate ROS

• Examples:

  • Ferritin

  • Caeruloplasmin

Antioxidant enzymes

Protection Against Damage

• Last line of defense to ROS

• Function: Neutralize ROS that have escaped previous protections

• Examples:

  • Super dismutase (SOD)

  • Catalase

  • GSH peroxidase

DNA

Are there more mechanisms to repair damaged DNA or proteins?

protelytic cleavage

Irreparable proteins are eliminated via _______

Ubiquitin

Damaged proteins are tagged with _______ to show that they need to be removed

Proteasome

for smaller ???

Lysosomal pathway

for medium ??

Autophagy

Gets ride of large aggregates and damaged organized

No

Beyond vitamins, are there damage repair systems for lipids?

Bacterial Infection Effects:

• Compete with host cell for extracellular nutrients

• Impact extracellula pH and compromise heomeostasis

• Accumulate toxic waste

Viral Infection Effects:

• Co-opts the host’s endoplasmic reticulum for replication and maturation, created signficant stress and increased host demand for protein synthesis

• OTHEr

Autophagy

Cellular protective pathway which removes damaged cellular components

Use lyosome to degrade and recycle large components

Key for antimicrobial defense