Lecture 3: Necrosis Flashcards
At what point does definite cell death occur?
When the threshold of accumulated damage is passed.
What usually initiates the cascade of accumulated damage?
Ischaemia due to hypoxia and hypoglycaemia - The lack of O2 and nutrients coming into the cell due to the failure of a blood supply
Describe briefly the different molecular mechanisms when there is accumulated damage in cells exposed to injury:
DAMAGE TO CELL MEMBRANE AND MITOCHONDRIA.
No ATP synthesis due to ischaemia; anaerobic respiration takes over to provide energy and glycogen is used.
Once glycogen stores are depleted, no energy is made, and ATP-dependent Na+ K+ pumps, as well as Ca2+ pumps, fail.
Na+ accumulates in the cell, and with it, H2O, which causes swelling.
The influx of Ca2+ into the cytosol occurs as its entry into the cell is now uncontrolled due to the failing pump which usually removes Ca2+ from the cell.
Free Ca2+ in the cell activates cytosolic enzymes and this causes the most destruction;
protein kinases will cause phosphorylation of other proteins,
phospholipases will attack membrane lipids and cause dissolution,
and calpain proteases disassemble cytoskeletal proteins.
Fully explain what happens when there is an interference in the supply of energy to the cell i.e. during ischaemia
Cellular energy metabolism is altered. Ischaemia compromises mitochondrial function, (important for ATP synthesis, aerobic respiration) and because it depends on oxygen and glucose for energy, oxidative phosphorylation cannot occur therefore anaerobic respiration will occur, and glycogen will be used for energy. As a consequence, glycogen stores will be used up and there will be a lower pH due to the production of lactic acid.
The capacity of the cell to make ATP will soon be exhausted.
What happens in normal cells that maintain Na+/K+ homeostasis?
Normally under resting conditions, Na+ leaks into the cell and K+ leaks out of the cell, and the concentration gradient is maintained by an energy-dependent Na+/K+ membrane pump which uses ATP to actively pump Na+ out of the cell and K+ back into the cell.
What happens to the concentration gradient of Na+ and K+ when there is injury to the cell membrane/no ATP available?
As the Na+/K+ membrane pump is energy dependent, failure of ATP production means the failure of the pump. Therefore Na+ cannot be removed from the cell and it accumulates inside the cell - at the same time H2O also rushes into the cell and causes swelling of internal membrane systems.
What happens in normal cells that maintain Ca2+ homeostasis?
Usually, in normal cells, Ca2+ is bound to buffering proteins and contained in ER and mitochondria, and the normal concentration of Ca2+ in the cytosol is very low compared to extracellularly due to the action of the ATP-dependent Ca2+ pumps.
What are free radicals?
They are reactive Oxygen species that are characterised by unpaired electrons in their outer shell, which makes them very reactive
What damage do free radicals cause?
They can cause
peroxidation of lipids which increases membrane permeability;
thiol-containing protein damage which causes ion pump damage;
DNA damage which fragments the DNA strands and impairs protein synthesis;
mitochondrial damage which causes mitochondrial depletion of NADPH and Ca2+ influx into the cell
How are we protected from the damaging nature of free radicals?
Protected by protective systems that depend on adequate nutrient supply such as from antioxidants and enzymes that neutralise free radicals to molecules of water.
What are free radicals produced by?
Free iron/copper in cells
Irradiation
Fenton reaction
