T2 L4 Mitochondrial myopathies Flashcards
How many copies of the genome in each mitochondria?
5-10
How many mitochondria are in a cell?
Between 2 and 2000
Describe maternal inheritance of mitochondria
Embryo derives all of its mitochondria from the egg
The mitochondria are in the tail of the sperm so aren’t absorbed on fertilisation
Any paternal mitochondria that do enter the egg are destroyed
What does the mitochondrial genome code for?
13 of the respiratory chain proteins
2 rNA
22 tRNA
What is the major producer of ROS?
The respiratory chain
Describe ROS
Reactive oxygen species
Highly reactive - sometimes due to the presence of unpaired valence shell electrons
What genome suffers the greatest exposure to & damage by ROS
Mitochondrial genome
Mitochondrial DNA is less effective at correcting mistakes & repairing mitochondrial DNA damage so defects can accumulate with age due to oxygen free radicals
What are some important electron carriers?
NAD+/NADH
NADP/NADPH
FAD+/FADH2
What are some reactive oxygen species?
Superoxide anion Hydroxyl radical Peroxide ion Hydrogen peroxide Hydrochlorus acid
Why does the efficiency of oxidative phosphorylation decline with age?
Due to the accumulation of mutations to mitochondrial DNA by ROS
Oxidative phosphorylation enzyme defects are strongly implicated in Alzheimer’s, Parkinson’s & type II diabetes
What are mitochondrial diseases?
Diseases arriving from defects in mitochondrial enzymes & systems
Major defects are incompatible with life so the affected embryos rarely survive
What is a myopathy?
Muscle disease
What is encephalomyopathy?
Mitochondrial disease causing muscular & neurological problems
What tissues are less able to tolerate lowered ATP production?
Neurons
Myocytes
Skeletal muscle cells
Beta cells of the pancreas
What are mitochondrial myopathies?
Group of muscular diseases
Mostly occur before the age of 20
Often begin with exercise intolerance or muscle weakness
What are some other symptoms of mitochondrial myopathies?
Heart failure / rhythm disturbances Dementia Deafness Blindness Seizures
Describe the threshold effect
When the level of mutant mitochondrial exceeds a certain threshold the cell then expresses dysfunction
What is homoplasmy?
The copies of mitochondrial DNA are all identical
What is heteroplasny?
Both normal & mutant mitochondrial DNA are present
What are the different types of mitochondrial myopathies?
Lebers hereditary optic neuropathy (LHON)
Myoclonus epilepsy with ragged-red fibre (MERRF)
Mitochondrial encephalomyopathy lactic acidosis & stroke-like episodes (MELAS)
Kearns-Sayre syndrome (KSS)
What is Lebers hereditary optic neuropathy?
Single base change in mitochondrial gene ND4 from Arg to His in a polypeptide of complex I
Mitochondria are partially defective in electron transport from NADH to UQ
Some ATP is produced by electron transport from succinate but not enough to support the very active metabolism of neurons
Results in damage to optic nerve leading to blindness
Single base change in mitochondrial gene for cytochrome b in complex III also produces LHON
What is myoclonus epilepsy with ragged-red fibre?
Caused by a point mutation in the mitochondrial gene encoding a tRNA specific for lysine. Usually at position 8344 in the mitochondrial genome for more than 80% of cases.
Many other genes are involved:
- Mt-TK
- Mt-TL1
-Mt-TH
-Mt-TF
Disrupts the synthesis of proteins that are essential for oxidative phosphorylation (ATP synthesis)
Skeletal muscle fibres have abnormally shaped mitochondria
Ragged red fibres due to clumps of mitochondrial that accumulate in aerobic skeletal muscle fibres.
What stain is used for the ragged red fibres?
Gomori modified Trichrome
What is mitochondrial encephalomyioathy lactic acidosis & stroke-like episodes (MELAS)?
Primarily affects the brain & skeletal muscle
Gene dysfunction involving Mt ND5 complex, Mt-TH, Mt-TL1, Mt-TV
Symptoms appear in childhood
What are the symptoms of MELAS?
Build up of lactic acid Stroke-like episodes with muscle weakness Seizures leading to loss of vision Movement difficulties Involuntary muscle spasms (myoclonus) Dementia
What is Kearns-Sayre syndrome (KSS)?
Results from a 5kb deletion of mitochondrial genome
Onset before the age of 20
Affected patients have a short status & often have multiple endocrinopathies including diabetes
What are the symptoms of KSS?
Dementia
Retina pigmentosa - group of genetic eye conditions in which abnormalities of rods & cones or the retinal pigment epithelium eventually lead to blindness
Lactic acidosis
Heart conduction defects
Raised cerebrospinal fluid protein content
What is the treatment for mitochondrial myopathies?
Prognosis is variable & dependent on the type of disease & the patient’s metabolism
Occupational / physical therapy may extend the range of muscle movement
Vitamin therapies may improve function - Rivoflavin, creatine, CoQ, C, K, carnitine
No specific treatments
How do you prevent mitochondrial myopathies?
IVF strategy to replace defective mitochondria inherited from a mother
Merge DNA from 2 fertilised eggs
Mitochondrial gene replacement
Maternal spindle transfer
What is the process of mitochondrial gene replacement (pronuclear stage)?
1) Patient’s egg with abnormal mitochondria is fertilised with the partner’s sperm
2) Patient’s zygote has abnormal mitochondria
3) Patient’s pronuclei is removed from the zygote & transferred to enucleated egg which has normal mitochondria
4) Cleaving embryo with normal mitochondria & maternal & paternal genome can be transferred to the uterus
What is the process of maternal spindle transfer?
1) Unfertilised patient’s egg with abnormal mitochondria
2) Spindle & associated chromosomes are removed as karyoplast from patient’s egg & fused into enucleated donor egg
3) Reconstituted egg is fertilised with sperm from the patient’s partner
