Mitochondrial Myopathies Flashcards
What did mitochondria evolve from?
- bacteria
How is mitochondrial DNA organised and how many copies does each mitochondria posses?
- circular (DNA is double helix)
- hundreds of copies in each matric of mitochondria
Mitochondria are maternally inherited, what does this mean?
- only passed on my mother
- mitochondria in sperm do not enter the egg, if they do the =y are destroyed
In each mitochondria there are 5-10 copies of each mitochondrial DNA. How is the mtDNA organised?
- closed circular double stranded molecule
How large is the human mitochondria genome?
- 16.5 thousand base pairs
Are the majority of mitochondrial proteins produced by nuclear or mitochondrial DNA?
- nuclear
- proteins created in cytosol and transported into mitochondria
Although a lot of the mitochondrial genes have evolved into the nuclear DNA, how many respiratory proteins are encoded within the mitochondrial genome?
- 13
- complexs in electron transport chain etc..
Although a lot of the mitochondrial genes have evolved into the nuclear DNA, the mitochondrial genome still codes for 13 of the respiratory proteins. As mitochondria contain their own genes for respiratory proteins they also need their own transcription and translation processes. How many ribosomal RNA (rRNA) and transcriptomic RNA (tRNA) does the mitochondrial genome code for?
- 2 rRNA (synthesises proteins)
- 22tRNA (involved in protein translation)
The respiratory chain, also known as the electron transport chain is the main producer of ATP, but is also the main producer of what dangerous products?
- reactive oxygen species
The respiratory chain, also known as the electron transport chain is the main producer of reactive oxygen species in the mitochondria. Due to this what in the mitochondria can be damaged due to the close exposure?
- mitochondrial genome
- mtDNA less effective at correcting mistakes and repairing mt DNA damage
The respiratory chain, also known as the electron transport chain is the main producer of reactive oxygen species (ROS) in the mitochondria. Due to this the mt genome can be damaged by the ROS, and mtDNA becomes less effective at correcting mistakes and repairing mt DNA damage. What can this then cause and in which patients is this most common?
- increases risk of defects and mt mutations
- mtDNA defects accumulate with age
- mt DNA mutates more rapidly (x 10-fold) than nuclear DNA
Reactive oxygen species (ROS) can be created in the mitochondria, where will the majority of these ROS be created?
- electron transport chain in matrix and intermembrane space
- especially in complexes 3 and 4
Reactive oxygen species (ROS) can be created in the mitochondria, why are ROS created?
- electrons move to where they should not be
What happens to oxidation respiration as we age?
- declines in function
- in part due to mtDNA mutation accumulation
What is a common link between Alzheimer’s / Parkinson’s and type II diabetes in relation to the mitochondria?
- oxidative phosphorylation enzyme defects
What tissues are most affected by defects or mutations in oxidative phosphorylation?
- tissues with high metabolic need
- neurological, skeletal are examples
How common are diseases that arise from defects in mt enzymes and systems such as the citric acid cycle and oxidative phosphorylation?
- rare and a lot are incompatible with life
Diseases that arise from defects in mt enzymes and systems such as the citric acid cycle and oxidative phosphorylation predominantly affect which 2 systems in the body?
1 - CNS
2 - musculoskeletal system
A number of human diseases are attributed to mutations in mt genes that reduce the capacity of cells to produce ATP. What specialities is mitochondrial diseases classed as and what is often the most common clinical presentation?
- neurological disease
- exercise intolerance or muscle weakness
A number of human diseases are attributed to mutations in mt genes that reduce the capacity of cells to produce ATP. In addition to exercise intolerance what are some other common clinical presentations of mitochondrial disease?
- heart failure / rhythm disturbances
- dementia and seizures
- deafness
- blindness
What age does mitochondrial disease normally present before?
- 20 years old
What is heteroplasmy and monoplasmy?
- heteroplasmy = more than one type
- monoplasmy = all the same
What is the threshold in mitochondrial disease between the heterolpasmy for healthy and diseased mitochondria?
- 70%
- above 70% patients present with clinical symptoms
When do mitochondrial mutations start?
- in primordial germ cells
- primary undifferentiated stem cell type that will differentiate towards spermatozoa or oocytes in males and females, respectivley.
What is the mitochondrial genetic bottleneck?
- a selected number of mtDNA molecules are transferred into each oocyte
- oocyte maturation is associated with rapid replication of this mtDNA population
- restriction-amplification event can lead to a random shift of mtDNA mutational load between generations
- this accounts for variable levels of mutated mtDNA observed in affected offspring from mothers with pathogenic mtDNA mutations
According to Mt genetic bottleneck in a mother who has 33% mt mutation load, does this mean all offspring could have the same level of mutation load?
- no
- could have 25, 50 or 75% mutation load
- mutation load increases with age
Mt myopathies can be biochemically classified into 5 groups, what are they?
1 - mitochondrial transport system deficiencies
2 - defects in substrate utilisation (FA oxidation)
3 - defects of TCA cycle
4 - defects of oxidative phosphorylation coupling
5 - Defects of oxidative phosphorylation (all complexes)
A mutation in which complex causes Lebers hereditary optic neuropathy (LHON)?
- single base change in mt gene ND4 in complex I
- partially defective in electron transport from NADH to Ubiquinone
What mutation can cause myoclonus epilepsy with ragged-red fibre disease (MERRF)?
- point mutation in the mitochondrial gene that encoding a tRNA specific for lysine (tRNALys)
- protein translation is disrupted and no proteins made
- specifically those involved in oxidative phosphorylation
A single base change in mt gene ND4 in complex I that causes a partial defective in electron transport from NADH to Ubiquinone can cause Lebers hereditary optic neuropathy (LHON). A mutation in which other complex can also cause LHON disease?
- a single base change in the mt gene for cytochrome B in complex III also produces LHON
A single base change in mt gene ND4 in complex I that causes a partial defective in electron transport from NADH to Ubiquinone can cause Lebers hereditary optic neuropathy (LHON). Although complex 2 can pass some electrons into the electron transport chain from FADH2, this does not provide sufficient ATP and leads to damage of which nerve?
- the optic nerve and leads to blindness
What is the histological diagnosis of myoclonus epilepsy with ragged-red fibre?
- skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria
What is the gold standard for mitochondrial disease?
- skeletal muscle biopsy
What can we look for in urine/blood to diagnose mitochondrial disease?
- lactate levels
In addition to muscle biopsy, urine and blood samples, what other method casn be used to diagnose mitochondrial disease?
- genetic testing
Prognosis can vary in mitochondrial disease, depending on the type of disease and the patient’s metabolism (varies greatly between individuals). What are some of the common treatments?
- occupational / physical therapy
- vitamin therapies such as riboflavin, creatine, CoQ, C, K and carnitine may improve function for some
- THERE IS NO CURE
What is the IVF strategy that is being used to try and cure mitochondrial disease?
- healthy donor egg and mother mutated egg fertilised by father
- mutated fertilised pronuclei removed and transplanted to healthy egg
- mutated mitochondria are left in oocyte
In the Maternal spindle transfer treatment as an option to try and cure mitochondrial disease, how does this work?
- spindles and associated chromosomes removed from healthy donor egg
- spindles and associated chromosomes removed from mutated egg and implanted into donor egg
- egg is then fertilised
