Mitochondrial Disorders - Week 3 Flashcards
What is the main role of mitochondria?
Bonus question: What does pot of greed do?
It’s the powerhouse of the cell
pot of greed lets you draw two cards
What is the shape/structure of the inner membrane of mitochondria?
The inner membrane is folded to form ‘cristae’
cristae = are ridges/crests
What type of replication do mitochondria undergo? What do they require for this?
Mitochondria replicate similar to bacteria (binary fission)
Mitochondria is dependent on the nucleus to replicate and grow
Other than powerhouse of the cell, list the range of basic roles that mitochondria plays that is critical for cell integrity and survival.
- reactive species generation and scavenging
- calcium regulation
- steroid biosynthesis
- nucleotide metabolism
- regulation of intermediary metabolism
- initiation of apoptosis
What locations in the eye have a high density of mitochondria?
- RGC and NFL
- Plexiform layers
- Photoreceptors
- Optic Nerve
Where are mitochondria found in myelinated regions of ganglion cell nerves?
In myelinated regions, mitochondrion are limited to regions of Nodes of Ranvier, where energy is required for the continuous propagation of action potentials
What parts of the eye can be affected in mitochondrial disease?
- extraocular muscles
- levator muscle
- lens
- retina
- optic nerve
way to remember: LROLE
What are the two types of mitochondrial disease? Describe them.
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
How are mitochondrial diseases inherited?
Maternal inheritance
Which type of hereditary optic neuropathy is the most common?
Dominant optic atrophy
Name 4 ocular manifestations of mitochondrial disorders
Dominant Optic Atrophy
Leber’s Hereditary Optic Neuropathy
Chronic Progressive External Ophthalmoplegia (CPEO)
Secondary mitochondrial disorders
What is the energy efficiency of mitochondria?
70%. Highly efficient
Name the primary energy process for all aerobic organisms
Oxidative phosphorylation
Which cells in the cornea require a lot of energy?
Endothelial cells
Do photoreceptors and cardiomocytes contain lots or few mitochondria?
Lots. Thousands
How many mitochrondria do keratinocytes contain?
only a few
Where in the mitochondria does the TCA cycle take place? Where does the ETC process take place?
TCA = in the ECM ETC = in the membrane
Which ETC complexes are important for pumping protons from the matrix to the inter-membrane space? And what does this achieve?
Complexes I, III, and IV. This creates an electrochemical gradient across the inner membrane which enables the synthesis of ATP
Where are mitochrondria found in myelinated regions of ganglion cells?
lmiited to regions of Nodes of Ranvier
How will offspring inherit mitochrondrial diseases?
100% of offspring inherit from a diseased mother. 0% from a diseased father
Describe Dominant Optic Atrophy, including it’s prevalence, it’s gender distribution, and what parts of the eye it affects?
1:12,000 prevalence. A degenerative disorder affecting rGCs and nerve fibre layer. Equally affects males and females
Describe the loss of VA over time in Dominant Optic Atrophy (DOA)
VA decreases over the first 2 decades of life
What are the clinical signs of dominant optic atrophy?
- saucerisation of optic disc
- C:D ratio greater than 0.5
- peripapillary atrophy
- sectoral pallor of optic nerve
What is the cause of dominant optic atrophy?
Mutation in OPA1, a GTPase nuclear gene
What is OPA1 involved in?
mitochondrial membrane fusion, energy metabolism, control of apoptosis (cytochrome C), calcium clearance
What complexes in the ETC are affected by OPA1? (and therefore would be affected in DOA)
Complexes I, II and III
How can OPA1 deficiency affect on-centre RGCs
leads to selective dendritic pruning of on-centre RGCs. (i.e. less dendrites)
Describe Leber’s heriditary optic neuropathy, including it’s onset, whether it affects one or both eyes, pain, and vision loss
Acute onset. Bilateral. Painless. Central vision loss over days to months
What is the prevalence of Leber’s? Males vs Females?
1:25,000. Males affected 5 times more than females
What causes the majority of Leber’s cases?
3 mtDNA point mutations within the mitochondrial respiratory chain complex 1 subunit genes
Describe the clinical appearance of the fundus in Leber’s
- disc hyperemia
- corkscrew vessels
- relative opacity of NFL
How would you give further diagnostics for Leber’s patients?
- family history
- gene testing (mt mutations)
When is the onset of Chronic Progressive External Ophthalmoplegia (CPEO)?
Childhood or up to 30yrs old
List the symptoms of CPEO
- lid ptosis
- strabismus
- disjunctive eye movements
- ophthalmoplegia
- pigmentary retinopathy (salt + pepper fundus)
- RPE high energy tissue
What percentage of CPEO patients exerience pigment degeneration?
2.5%
Describe what happens to the extraocular muscles in CPEO
Very significant atrophy of superior rectus muscle. Other muscles also have atrophy but not as much
List 2 diseases that can cause secondary mitochondrial dysfunctions, and explain how?
- AMD: RGCs from AMD patients have more mtDNA rearrangements and deletions; these re-arrangements accumulate over time
- Glaucoma: mechanical stress on mDNA. Optic nerve is packed with mitochondria, therefore susceptible to dysfunction
How might Diabetic Retinopathy cause mitochondrial dysfunction?
Progressive mtDNA damage with hyperglycemia
Is keratoconus associated with damaged mtDNA?
yes
