Cellular Responses Flashcards
Mechanisms of Cellular Injury
things that occur in cells secondary to cause of damage/stimuli:
1) decreased ATP
2) mitochondrial damage
3) entry of Ca2+
4) increased ROS
5) membrane damage
6) protein misfolding + DNA damage
can occur simultaneously in same cell
a lot of cross-talk/intertwining of these mechanisms
ATP Production
1) Oxidative Phosphorylation -> requires O2 (aerobic respiration)
- occurs in mitochondria
- ADH -> ATP (NADH + FADH from kreb’s)
- more efficient + better system
- disadvantages = produces toxic byproducts (reduced Oxygen = free radical)
2) Glycolysis -> no oxygen (anaerobic respiration)
- occurs in cytoplasm
- glucose -> ATP
- terribly inefficient system
- produces lactic acid as toxic byproduct
need oxygen for more efficient production of ATP
Major Causes of ATP Depletion
1) **decreased O2 + nutrients **
- ischemia
- heart failure
- respiratory failure
- reduced oxygen carrying capacity in blood (anemia or CO toxicity)
2)** mitochondrial damage**
3) specific targeting of ATP-generating mechanisms by toxins
Consequences of depleted ATP
ATP used for tons of vital cellular functions
depletion of ATO to 5-10% of normal levels has widespread effects
Influx of Calcium
calcium ions = important mediators of injury -> keep them contained
- free Ca in cytoplasm maintained at very low conc.
- IC Ca mainly kept in mito + ER
during cell injury, intracytoplasmic Ca levels INCREASE
- increased influx from EC sources d/t increased membrane permeability
- release from mito + ER
multiple downstream effects of increased Ca:
- opening of mitochondrial permeability transition pore -> decreased ATP
- activiation of numerous enzymes resulting in membrane + nuclear damage as well as further depletion of ATP
Mitochondrial Damage
damage may occur by:
- increased cytosolic Ca
- ROS
- oxygen deprivation
- mutations in mitochondrial genes (inherited dz)
mitochondrial damage = opening of transition pore
downstream effects generally necrosis v apoptosis
Free Radicals + Reactive Oxygen Species
free radicals = chemicals that have an unpaired electron in their outer orbit -> unstable
when FR collide with nearby mol, energy is expelled + can cause damage
- proteins, CHO, lipids, nucleic acids
molecules disrupted by FR can become unstable + propagate process (autocatalytic reaction)
generation of free radicals:
- normal metabolic + mitochondrial resp
- absorption of radiant energy
- inflammation
- enzymatic metabolism of exogenous chemicals/drugs
- transition metals
- nitrix oxide
Mechanisms to keep them in place:
- spontaneous decay
- antioxidants
- iron + copper-based transport proteins
- series of enzymes comprising the radical-scavenging system = catalase, superoxide dismutase, glutathione peroxidase
damage related to free radicals occurs d/t imbalance -> oxidative stress
- too much FR production
- depletion/disruption of scavenging systems
What are membranes made of?
- phospholipids
- very polar
- transport + signaling proteins + carbs
- physical barrier + cell structure
applies to mitochondrial + lysosomal membranes
Membrane Damage
Damage can occur by:
- ROS (lipid perodixation)
- decreased phospholipid synthesis
- increased phospholipid breakdown
- cytoskeletal abnormalities
Consequences:
1) mitochondrial damage
- decreased ATP synthesis
- opening of transition pore -> release of proteins trigerring apoptosis
2) lysosomal injury
- release of enzymes into cytoplasm -> free to degrade normal functioning enzymes
3) plasma membrane leakage
- loss of osmotic balance -> swelling
- leakage of metabolites needed to generate ATP
- leakage of constituents of cell that can be detected on BW
Damage to DNA + Proteins
DNA repair mechanisms exist but may not be enough to repair damage or may induce further mutations
- irreperable damage -> apoptosis
damaged or misfolded proteins can be broken down + recycled or may trigger apoptosis
