Mitochondria in Neurodegeneration

Question 1

mitochondria function

Answer 1

Oxidative phosphorylation
Calcium homeostasis
Apoptosis
Fatty acid oxidation

Question 2

What determines mitochondria function ?

Answer 2

Shape

Question 3

Motor Neuron Disease

Answer 3

• Adult onset, rapidly progressing, neurodegenerative disease
• Characterised by loss of both upper and lower motor neurons (MN)
• Muscle wasting & paralysis
• Death 2-3yrs from onset

Question 4

MtDNA in PD

Answer 4

• Possible association with particular haplogroups of mtDNA
• Secondary mtDNA deletion rates increased in post mortem tissue
• Link between function and mtDNA??
• possible target for therapy

Question 5

Mitochondrial morphological abnormalities

Answer 5

SOD1 gene mutation

Often complexes 2 and 4 identified

Question 6

Mitophagy in PD

Answer 6

Parkin and PINK1 function in the same pathway- both cause early onset Parkinsons
PINK1 recruits parkin to depolarised mitochondria
parkin interacts with p62 to tag the mitochondria to undergo mitohpagy

PINK1 Acts as a sensor on mito mem but constitutively degraded

Question 7

Oligomycin

Answer 7

inhibits complex 5 of Resp chain

Question 8

HD-

Answer 8

• Hyperkinetic choreiform movements
• Pathology in the striatum
• Mutant huntington
• CAG triplet repeat extensions which are pathogenic
• Possible mechanisms include
endocytosis, intra-neuronal trafficking, transcriptional regulation, mitochondrial function

Question 9

HD post mortem

Answer 9

Post mortem -CII defects prominent
MtDNA changes – reduced in HD
Morphology changes – less fold in the cristae
Changes in peripheral tissues as well

Question 10

What process do fibroblast used for 95 % of their energy production?

Answer 10

Glycolysis

Question 11

What energy process do neurons mainly rely on ?

Answer 11

Oxidative Phosphorylation

Question 12

HD animal models

Answer 12

• Mutant htt and WT htt localise to the OMM
• Ultrastructural changes
• CII defects found only in symptomatic animals – in striatum
• Mthtt reduces O2 consumption – correlates to CAG repeat length

Question 13

Parkinsons Disease

Answer 13

• Most cases are sporadic
• Familial form due to mutations in several identified genes
autosomal recessive – parkin, PINK1, DJ1
autosomal dominant – α synuclein, LRRK2
• Pathogenesis 3 main pathways
oxidative stress
proteasome dysfunction
mitochondrial dysfunction
• Interplay between environmental
and genetic factors
loss of dopaminergic in SN

Question 14

Autosomal Recessive

Answer 14

parkin, PINK1, DJ1

Question 15

Autosomal Dominant

Answer 15

α synuclein, LRRK2

Question 16

3 Pathways of Pathogenesis

Answer 16

oxidative stress
proteasome dysfunction
mitochondrial dysfunction

Question 17

toxin induced mitochondrial dysfunction –

Answer 17

Exposure to pesticides/Herbicides 
-	MPTP 
-	Rotenone 
-	Paraquat 
Toxin can induce systemic 
But neuron affected are the dopaminergic

Question 18

Fibroblasts from Parkin patients

Answer 18

Reduction in complex 1

ATP production red when introduced at complex 1

Question 19

PINK1 models

Answer 19

Massively hyperfused mitochondrial network in fibroblast mutants
PINK1 modes – mitochondrial defects
-PINK1 Mice models don’t show neurodegenerative loss but rat models do

Question 20

Master regulator TF and HD

Answer 20

PGC-1 Alpha

Reduced in HD – down reg

Question 21

What does Oxidative Phosphorylation use ?

Answer 21

• Repsiratory chain complexes
• Coenz Q
• Cytochrome C electron acceptor in the chain

Question 22

Oxidative Phosphorylation

Answer 22

1. Redox of NADH+H+ at Complex 1- 4 protons pumped from matrix to inter membrane space
2. Redox of FADH2 at complex2 Coenz Q picks up electrons from 1 &2 and takes to comple 3
3. Redox of Complex3 4 protons pumps from matrix to intermembrane space. carrier C transports electrons to complex 4
4. ATP synthase reaction - pumps protons from intermembrane space to matrix and produces ATP from ADP+ Pi + energy

Question 23

1,3 and 4 main component

Answer 23

of electrochemical gradient in the mitochondrial membrane which is then used by complex 5

Question 24

Mitochondrial action

Answer 24

• Constantly undergo fission and fusion events
• Form an elaborate network in some cell types
• Both inner and outer membranes must undergo fission and fusion events
• Mitochondrial morphology correlates with mitochondrial function

Question 25

Mitochondrial degradation

Answer 25

Autophagy – Bulk
Or Ubiquitin – proteasome selective
Mix of both starts selective but whole organelle degraded by autophagosome

Question 26

Neurodegenerative Disease

Answer 26

• Increasing prevalence with age