Mitochondrial Dysfunction

Question 1

What happens when mitochondria is dysfucntional

Answer 1

Membrane potential is depolorised
Cannot undergo membrane fission - so will be targeted for mitophagy (cell death)

Question 2

Whihc brain region affected in PD?

Answer 2

Substantia nigra

Question 3

PINK1 Location

Answer 3

On the outer mito membrane
Depolarized mitochondria are tagged for mitophagy by retention of PINK1 on the OMM

Question 4

What happens to PINK-1 protein in healthy mitochondria?

Answer 4

Negetive membrane potential of mito (-150mv) sucks in the protein to degrade it.

Question 5

What happens to PINK-1 when the mito is dysfunctional? (Initial step)

Answer 5

Now has a depolorised +ve MP so the PINK1 protein accumilates on the surface

Question 6

Which to proteins are invovled in PD and Mito dysfucntion?

Answer 6

Parkin
PINK-1

Question 7

Duchen- How does Cychlophilin D and mPTP link to AD?

Answer 7

Amyloid beta may bind to cyclophilin D

Question 8

What are the 3 energy sources of the cell? and how much ATP?

Answer 8

1. Glycolysis - 2 atp
2. TCA- 2 atp
3. Electron transport chain - ATP synthesised - 32-46 atp molecules

Question 9

Apart from producting ATP, other cellular roles of mitochondria?

Answer 9

• Calcium homeostasis
• Apoptosis
• ROS production

Question 10

Which cell type is mitochondria most important for?

Answer 10

Neurons

Question 11

Which cycles do neurons mostly use to generate ATP?

Answer 11

TCA cycle
ETC

Question 12

What are the 8 enviromental risk factors for PD? which is most relevent
Which factor is slightly protective?

Answer 12

AGE - most relevent
gender
Pesticide exposure
MPTP
Rural leaving
Prior head injsury - TBI
Smoking - slightly protective
Coffee

Question 13

What are the 6 genetic risk factors for PD

Answer 13

Alpha-synuclein
LRRK2
DJ-1
Parkin
PINK1
ATP13A2

Question 14

Mutations in the XXXXXX gene are the most common genetic cause of both familial and sporadic PD

Answer 14

LRRK2

Question 15

Sex differences

Answer 15

More males than females affected

Question 16

Describe Reactive Oxygen Species

Answer 16

Highly reactive small ions which help signalling at LOW levels

Question 17

Which signalling pathways are ROS apart of?

Answer 17

1.NF-kB inflamamtory & Immune
2.MAPK pathway Pro-apopotic
3.PI3K-Akt Cell survival & growth
3. Keap1 Invovled in cellular response to oxidative stress

Question 18

Effects of high levels of ROS?

Answer 18

Damages nucleic acid, proteins and lipids - one of the major concequences of mitochondiral dysfunction & oxidative stress

Question 19

ROS is a natural by product of

Answer 19

Mitochondrial respiration

Question 20

Define oxidative stress

Answer 20

Accumilation of ROS …finish

Question 21

ROS needs to be maintained at..

Answer 21

low levels

Question 22

How are ROS generated?

Answer 22

In the ETC - with a leak
With Oxygen and free electrons

Question 23

Are all ROS toxic?

Answer 23

No

Question 24

Describe how ROS are maintained at low levels?

Answer 24

Antioxidants either collects or convert ROS into less toxic form

Question 25

What molecules maintain ROS at low levels?

Answer 25

Antioxidants like enzymatic SOD, CAT,GPx Non-enzymatic antioxidants like Vit C, Vit E and glutathione

Question 26

Why is it harder to avoid toxic ROS as we age? 3 things

Answer 26

1. Including increased ROS production 2. Decreased antioxidant defense mechanisms 3. Impaired cellular repair processes

Question 27

Apart from anti-oxidants what other mechnsims gets rid of toxic ROS

Answer 27

Protein degradation (decreases as we age or stressors) so damaged proteins accumilates

Question 28

What does the ROS target

Answer 28

The 13 proteins of the ETC

Question 29

A shift toward ------ in aged cells encourgaes oxidative damage?

Answer 29

Mitochondrial Fission

Question 30

Older mitochondria produce and concequence of this

Answer 30

More ROS Less antioxidant Less ATP Makes you more vunreble to futher insult e.g. oxidative stress

Question 31

What are the 3 main sources of ROS in brain and neurons

Answer 31

Cytoplasm Plasma membrane Mitochondria

Question 32

Where is SOD1 mutated in ALS

Answer 32

In exons dominant and recessive mutations

Question 33

What does the antioxidant turn toxic ROS into?

Answer 33

LESS TOXIC FORM Hydrogen peroxide free radical H2O2

Question 34

What is MPTP? Bioenergetic dysfunction

Answer 34

Toxic drug inhibitor of complex 1 od ETC Drug induced PD

Question 35

What else inhibits complex 1 of ETC

Answer 35

Pesticides

Question 36

Excitatory (what is Mito role agaisnt this)

Answer 36

Buffering calcium Ca2+ homeostasis

Question 37

How does Mitochondria buffer calcium

Answer 37

Whne they is high Ca2+ in post-synaptic neuron. Mito takes it up and then slowly releases it back into cytoplasm to avoid Hyperexcitability

Question 38

What happens to mitochondria if Calcium is too high in post-synaptic cell?

Answer 38

Calcium overload leads to opening of mPTP and ROS production and cell death

Question 39

What is PINK1 important for

Answer 39

Calcium homeostatsis Quailty control through autophagy (damaged mito removed and recycled)

Question 40

How does PINK1 quality control

Answer 40

It detects damaged mitochondria and triggers their removal through mitophagy, which is a process of autophagy.

Question 41

What does familial PINK1 mutations do in PD?

Answer 41

Mutations in the PINK1 gene are a significant cause of familial Parkinson's disease. These mutations can disrupt mitophagy, leading to the buildup of damaged mitochondria and contributing to the disease's progression.

Question 43

Mutation in fusion protein & disease

Answer 43

MFN1 MFN2 - charcot marie tooth OPA1- Optic atrophy & RGC death

Question 44

Mutation in fusion proteins

Answer 44

DRP1 FIS1

Question 45

What is mitophagy

Answer 45

Mitochondrial quailty control - remove damaged mitochondria (depolorised and creating toxic ROS)

Question 46

What does Parkin do in PD?

Answer 46

While mutations in Parkin cause autosomal recessive PD, Parkin inactivation also plays a role in sporadic PD, potentially through nitrosative and dopaminergic stress.

Question 47

Parkin and PINK1 mitigate....

Answer 47

STING-induced inflammation Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA.