Mitochondira

Question 1

What is reperfusion injury

Answer 1

Worsening of ischaemic tissue injury when adequate blood flow is restored due to innate and adaptive immune response + apoptosis of cells initiated by mitochondria

Question 2

What happens to levels of cytochrome C in ischaemia and reperfusion

Answer 2

They rise (thought it could be used as a marker for post arrest reperfusion injury)

Question 3

What are the 4 ways cells die

Answer 3

Necrosis, apoptosis, autophagy, programmed necrosis

Question 4

What happens in necrosis

Answer 4

Membrane integrity is lost and ion transporters become dysfunctional.
Cell swelling and rupture
Release of toxic cellular components
Inflammatory response and death

Question 5

What stimulates cell death in RI

Answer 5

General proinflammatory environment
Oxidative stress
Cytotoxic stimuli

Question 6

Name some pro apoptotic proteins

Answer 6

Cytochrome C

Caspases

Question 7

What is autophagy

Answer 7

Removal of damaged organelles and oxidised proteins etc

Question 8

What happens in programmed necrosis

Answer 8

Necroptosis: protein kinases are activated to increase oxidative stress
Parthantosis: degradation of DNA within nucleus

Question 9

What affect does hyperoxia have on mitochondria

Answer 9

Further injury and damage

Question 10

In relation to RI and mitochondria, what does cooling patients do

Answer 10

Preserves mitochondria, stops MPTP opening, reduced apoptosis

Question 11

Why is the brain particularly prone to reperfusion injury

Answer 11

High metabolic rate
Poor ability to store ATP
Cerebral glycogen stores deplete within 5 minutes of arrest
Cerebral mitochondria have less cytochrome C oxidase (an antioxidant) so there’s increased spillover of superoxide species and more susceptibility to ROS

Question 12

What are the cardiac results of RI

Answer 12

Fibrosis

Arrhythmias due to a systolic Ca overload and resulting afterdepolarisations

Question 13

What happens to oxygen and pH on reperfusion

Answer 13

There is an influx of oxygen

pH normalises

Question 14

What is the pH paradox of RI

Answer 14

During ischaemia: acidosis with cell compensation mechanisms leading to raised intracellular Na
On reperfusion: H+ washout extracellularly leads to further Na influx to the cell. This high intracellular Na leads to a Ca influx and overload
Ca overload is one factor contributing to mPTP opening

Question 15

What factors lead to MPTP opening

Answer 15

ROS generation
Ca influx
Both of these directly influence mPTP opening + they lead to activation of inflammatory and thrombogenic cascades which also open mPTP

Question 16

What happens following MPTP opening

Answer 16

There is an influx of H and uncoupling of the ETC preventing ATP synthesis
There is disruption of cell structure
Osmotically driven water influx leads to cell swelling, rupture and death

Question 17

Intracellular calcium rises in RI following normalisation of pH, what is the result of this

Answer 17

Arrhythmias
Protease activation = cell damage and death
MPTP opening
Activation of inflammatory and thrombogenic cascades

Question 18

What does MPTP stand for

Answer 18

Mitochondrial permeability transition pore

Question 19

What does opening of the MPTP lead to

Answer 19

The inner membrane becomes permeable and the membrane potential is lost as a result. There is dissociation of oxidative phosphorylation and reduced ATP.
Apoptotic factors are released and there is cell death

Question 20

Name some potential drug therapies for reperfusion injury and how they work

Answer 20

Cyclosporine - inhibits MPTP opening
Haemoglobin - ROS scavenger
Ammonium tetrathiomolybdate (ATTM) - It’s a copper chelator which released sulfide. Sulfide inhibits mitochondria and reduces ROS production