Mitochondrial Disorders - Week 3

Question 1

What is the main role of mitochondria?

Bonus question: What does pot of greed do?

Answer 1

It’s the powerhouse of the cell

pot of greed lets you draw two cards

Question 2

What is the shape/structure of the inner membrane of mitochondria?

Answer 2

The inner membrane is folded to form ‘cristae’

cristae = are ridges/crests

Question 3

What type of replication do mitochondria undergo? What do they require for this?

Answer 3

Mitochondria replicate similar to bacteria (binary fission)

Mitochondria is dependent on the nucleus to replicate and grow

Question 4

Other than powerhouse of the cell, list the range of basic roles that mitochondria plays that is critical for cell integrity and survival.

Answer 4

• reactive species generation and scavenging
• calcium regulation
• steroid biosynthesis
• nucleotide metabolism
• regulation of intermediary metabolism
• initiation of apoptosis

Question 5

What locations in the eye have a high density of mitochondria?

Answer 5

• RGC and NFL
• Plexiform layers
• Photoreceptors
• Optic Nerve

Question 6

Where are mitochondria found in myelinated regions of ganglion cell nerves?

Answer 6

In myelinated regions, mitochondrion are limited to regions of Nodes of Ranvier, where energy is required for the continuous propagation of action potentials

Question 7

What parts of the eye can be affected in mitochondrial disease?

Answer 7

• extraocular muscles
• levator muscle
• lens
• retina
• optic nerve

way to remember: LROLE

Question 8

What are the two types of mitochondrial disease? Describe them.

Answer 8

Primary Mitochondrial Disease: direct impairment of mitochondrial functions by mutations in genes located in either mito dna or nuclear dna

Secondary: mitochondrial dysfunction resulting either from environmental factors and/or genetic disorders

Question 9

How are mitochondrial diseases inherited?

Answer 9

Maternal inheritance

Question 10

Which type of hereditary optic neuropathy is the most common?

Answer 10

Dominant optic atrophy

Question 11

Name 4 ocular manifestations of mitochondrial disorders

Answer 11

Dominant Optic Atrophy
Leber’s Hereditary Optic Neuropathy
Chronic Progressive External Ophthalmoplegia (CPEO)
Secondary mitochondrial disorders

Question 12

What is the energy efficiency of mitochondria?

Answer 12

70%. Highly efficient

Question 13

Name the primary energy process for all aerobic organisms

Answer 13

Oxidative phosphorylation

Question 14

Which cells in the cornea require a lot of energy?

Answer 14

Endothelial cells

Question 15

Do photoreceptors and cardiomocytes contain lots or few mitochondria?

Answer 15

Lots. Thousands

Question 16

How many mitochrondria do keratinocytes contain?

Answer 16

only a few

Question 17

Where in the mitochondria does the TCA cycle take place? Where does the ETC process take place?

Answer 17

TCA = in the ECM
ETC = in the membrane

Question 18

Which ETC complexes are important for pumping protons from the matrix to the inter-membrane space? And what does this achieve?

Answer 18

Complexes I, III, and IV. This creates an electrochemical gradient across the inner membrane which enables the synthesis of ATP

Question 19

Where are mitochrondria found in myelinated regions of ganglion cells?

Answer 19

lmiited to regions of Nodes of Ranvier

Question 20

How will offspring inherit mitochrondrial diseases?

Answer 20

100% of offspring inherit from a diseased mother. 0% from a diseased father

Question 21

Describe Dominant Optic Atrophy, including it’s prevalence, it’s gender distribution, and what parts of the eye it affects?

Answer 21

1:12,000 prevalence. A degenerative disorder affecting rGCs and nerve fibre layer. Equally affects males and females

Question 22

Describe the loss of VA over time in Dominant Optic Atrophy (DOA)

Answer 22

VA decreases over the first 2 decades of life

Question 23

What are the clinical signs of dominant optic atrophy?

Answer 23

• saucerisation of optic disc
• C:D ratio greater than 0.5
• peripapillary atrophy
• sectoral pallor of optic nerve

Question 24

What is the cause of dominant optic atrophy?

Answer 24

Mutation in OPA1, a GTPase nuclear gene

Question 25

What is OPA1 involved in?

Answer 25

mitochondrial membrane fusion, energy metabolism, control of apoptosis (cytochrome C), calcium clearance

Question 26

What complexes in the ETC are affected by OPA1? (and therefore would be affected in DOA)

Answer 26

Complexes I, II and III

Question 27

How can OPA1 deficiency affect on-centre RGCs

Answer 27

leads to selective dendritic pruning of on-centre RGCs. (i.e. less dendrites)

Question 28

Describe Leber’s heriditary optic neuropathy, including it’s onset, whether it affects one or both eyes, pain, and vision loss

Answer 28

Acute onset. Bilateral. Painless. Central vision loss over days to months

Question 29

What is the prevalence of Leber’s? Males vs Females?

Answer 29

1:25,000. Males affected 5 times more than females

Question 30

What causes the majority of Leber’s cases?

Answer 30

3 mtDNA point mutations within the mitochondrial respiratory chain complex 1 subunit genes

Question 31

Describe the clinical appearance of the fundus in Leber’s

Answer 31

• disc hyperemia
• corkscrew vessels
• relative opacity of NFL

Question 32

How would you give further diagnostics for Leber’s patients?

Answer 32

• family history

- gene testing (mt mutations)

Question 33

When is the onset of Chronic Progressive External Ophthalmoplegia (CPEO)?

Answer 33

Childhood or up to 30yrs old

Question 34

List the symptoms of CPEO

Answer 34

• lid ptosis
• strabismus
• disjunctive eye movements
• ophthalmoplegia
• pigmentary retinopathy (salt + pepper fundus)
• RPE high energy tissue

Question 35

What percentage of CPEO patients exerience pigment degeneration?

Answer 35

2.5%

Question 36

Describe what happens to the extraocular muscles in CPEO

Answer 36

Very significant atrophy of superior rectus muscle. Other muscles also have atrophy but not as much

Question 37

List 2 diseases that can cause secondary mitochondrial dysfunctions, and explain how?

Answer 37

1. AMD: RGCs from AMD patients have more mtDNA rearrangements and deletions; these re-arrangements accumulate over time
2. Glaucoma: mechanical stress on mDNA. Optic nerve is packed with mitochondria, therefore susceptible to dysfunction

Question 38

How might Diabetic Retinopathy cause mitochondrial dysfunction?

Answer 38

Progressive mtDNA damage with hyperglycemia

Question 39

Is keratoconus associated with damaged mtDNA?

Answer 39

yes